|Publication number||US5585069 A|
|Application number||US 08/338,703|
|Publication date||Dec 17, 1996|
|Filing date||Nov 10, 1994|
|Priority date||Nov 10, 1994|
|Also published as||CA2205066A1, DE69530796D1, DE69530796T2, EP0808456A1, EP0808456A4, EP0808456B1, US5593838, US5643738, US5681484, US5755942, US5858804, US5863708, WO1996015450A1|
|Publication number||08338703, 338703, US 5585069 A, US 5585069A, US-A-5585069, US5585069 A, US5585069A|
|Inventors||Satyam C. Cherukuri, Sterling E. McBride, Peter J. Zanzucchi|
|Original Assignee||David Sarnoff Research Center, Inc.|
|Patent Citations (76), Non-Patent Citations (97), Referenced by (461), Classifications (90), Legal Events (9) |
|External Links: USPTO, USPTO Assignment, Espacenet|
Partitioned microelectronic and fluidic device array for clinical diagnostics and chemical synthesis
US 5585069 A
A system for processing a plurality of tests or syntheses in parallel comprising a sample channel for moving samples into a microlaboratory array of a plurality of wells connected by one or more channels for the testing or synthesis of samples, a station for housing the array and an optical system comprising at least one light source and at least one light detector for measuring the samples in the array, and a means of electrically connecting the array to an apparatus capable of monitoring and controlling the flow of fluids into the array.
Samples are loaded from a common loading channel into the array, processed in the wells and measurements taken by the optical system. The array can process many samples, or synthesize many compounds in parallel, reducing the time required for such processes.
1. An apparatus for processing two or more samples in parallel comprising
an array comprising (a) two or more modules, wherein the modules each comprise two or more wells connected together by one or more connector channels, (b) a sample channel for each module connecting the module to a fluid source, wherein said two or more modules are separately connected to fluid sources that are not connected to other modules, and (c) a valve in a connector channel of each module, wherein the wells and channels are formed on a substrate and enclosed by one or more covers that are affixed to the substrate,
electrokinetic pumps to separately pump fluid in each module,
a station housing a support for the array, and
a controller electrically connected to the station for controlling the flow of fluids to the array.
2. The apparatus according to claim 1, wherein a well from each of two or more of the modules is a detection well wherein the cover enclosing the detection well is transparent and each such detection well is located in the same relative position within its module.
3. The apparatus according to claim 2, further comprising an optical detection device, wherein the optical detection device is alignable with the detection wells of the detection-well-containing modules.
4. The apparatus according to claim 1, further comprising an optical detection device, wherein the detection device monitors the optical density of a sample transferred to a module from the connected fluid source.
5. The apparatus according to claim 1, wherein the station further comprises a fluid pump, which is external to the array, for transmitting fluids to the array under the control of the controller.
6. The apparatus according to claim 1, further comprising a sample loading capillary tube that can be reversibly connected with the sample channel of a module.
7. The apparatus according to claim 6, further comprising a high density code affixed to the sample loading capillary tube.
8. The apparatus according to claim 1, wherein the array comprises a dielectric substrate or glass.
9. The apparatus according to claim 8, wherein the sample and connector channels of the array include a first channel and a second channel and the array is formed of at least a first layer, a second layer and a substrate layer sandwiched between the first and second layers, wherein portions of sample and connector channels are formed in the upper or lower surfaces of the substrate layer and the upper or lower openings of these channel portions are sealed by the adjacent first or second layer, and wherein at least a first portion of the first channel formed in the upper surface is joined to a second portion of the first channel formed in the lower surface by a cross-layer portion of the first channel that extends through the substrate layer.
10. The apparatus according to claim 9, wherein but for the switching of the first channel from the upper surface to the lower surface via the cross-layer portion of the first channel, one of the first or second portions would intersect with the second channel.
11. The apparatus according to claim 1, wherein the array comprises at least 4.71 modules per square centimeter.
12. The apparatus according to claim 1, wherein a pump is associated with each well.
13. The apparatus according to claim 1, wherein the modules are radially arranged about a central point within the array.
14. The apparatus according to claim 1, wherein at least one of the valves is an electrostatically or electromagnetically controlled valve that is controlled by the controller.
15. The apparatus according to claim 1, further comprising two or more fluid reservoirs each connected to wells in separate modules by a reservoir channel.
16. The apparatus according to claim 15, wherein the fluid reservoirs comprise plastic release containers.
17. The apparatus according to claim 1, wherein the controller is electrically connected to the array and controls the flow of fluids in each module and the opening and closing, of the valves.
18. A kit adapted for use in a PCR or nucleic acid hybridization assay comprising the apparatus of claim 1 and paramagnetic beads that non-selectively bind DNA and that fit into one or more wells of the array.
19. The apparatus of claim 1, comprising a loading channel for passing fluids into two or more modules in parallel.
20. An apparatus for processing two or more samples or synthesizing a plurality of compounds in parallel comprising:
(a) a substrate comprising two or more parallel modules which each comprise
(i) a sample channel for moving a sample into the module,
(ii) two or more wells,
(iii) one or more connector channels that connect all of the wells in a module, wherein the wells and channels are formed on a substrate and enclosed by one or more covers that are affixed to the substrate, and
(iv) an electrokinetic pump for pumping fluids through the channels;
(b) a support station for housing the microfabricated substrate, which support station comprises an optical system comprising a light source and a light detector; and
(c) a computer electrically coupled to the microfabricated substrate for monitoring and controlling the processing of the samples and which is programmed to monitor and control the electrokinetic pumps.
21. The apparatus according to claim 20, wherein the wells are parallelly arranged within the modules.
22. The apparatus according to claim 20, wherein a well from two or more of the modules is a detection well having a transparent wall and each such detection well is located in the same relative position within its module.
23. A kit adapted for use in a PCR or nucleic acid hybridization assay comprising the apparatus of claim 20 and paramagnetic beads that non-selectively bind DNA and that fit into one or more wells of the array.
This invention relates to a system comprising a partitioned microelectronic and fluidic array. More particularly, this invention relates to a system including an array of microelectronic and fluid transfer devices for carrying out various processes, including syntheses, screening and chemical diagnostic assays, in parallel, and method of making the array.
BACKGROUND OF THE DISCLOSURE
Traditional methods of making a homologous series of compounds, or the testing of new potential drug compounds comprising a series of like compounds, has been a slow process because each member of the series or each potential drug must be made individually and tested individually. For example, a plurality of potential drug compounds is tested by using an agent to test a plurality of materials that differ perhaps only by a single amino acid or nucleotide base, or have a different sequence of amino acids or nucleotides.
Recently the process has been improved somewhat by combining the synthesis of various compounds having potential biological activity, for example, and traditional semiconductor techniques. A semiconductor or dielectric substrate for example is coated with a biologic precursor having amino groups with a light-sensitive protective chemical attached thereto, and a series of masks are placed over the substrate, each mask having an opening. A coupling agent, such as a photosensitive amino acid, is illuminated through the opening, forming a particular compound by reaction with the amino compound. Additional masks are used with different coupling agents to form an array of different peptides on the substrate which array can then be tested for biologic activity. Suitably this is done by exposure of the array to a target molecule, such as an antibody or a virus. The array is exposed to a biologic receptor having a fluorescent tag, and the whole array is incubated with the receptor. If the receptor binds to any compound in the array, the site of the fluorescent tag can be detected optically. This fluorescence data can be transmitted to a computer which can compute which compounds reacted and the degree of reaction. This technique permits the synthesis and testing of thousands of compounds in days rather than in weeks or even months.
However, the synthesis of each coupling reaction is not always complete, and the yield decreases as the length of the biopolymer increases. The process of aligning a plurality of masks and forming openings in the masks in sequence requires careful alignment and takes time.
The above synthesis is made possible by two other recent technical developments that allow various manipulations and reactions on a planar surface. One is the detection and analysis of DNA fragments and their identification by reaction with specific compounds. Probes, RNA and DNA fragments can be resolved, labeled and detected by high sensitivity sensors. The presence or absence of DNA fragments can identify diseased cells for example.
Another step forward is the ability to separate materials in a microchannel, and the ability to move fluids through such microchannels. This is made possible by use of various electro-kinetic processes such as electrophoresis or electro-osmosis. Fluids may be propelled through very small channels by electro-osmotic forces. An electro-osmotic force is built up in the channel via surface charge buildup by means of an external voltage that can "repel" fluid and cause flow. This surface charge and external voltage produces an electro-kinetic current that results in fluid flow along the channel. Such electro-kinetic processes are the basis for a device described by Pace in U.S. Pat. No. 4,908,112 for example.
Thus real progress has been made using electrophoresis and/or electro-osmosis to move very small amounts of materials along microchannels. Such movement can be used for synthesizing very small samples of potential drug compounds in an array and testing very small amounts of materials for bioactivity. Further progress in fully automating the fluidic processes will result in the synthesis and testing of vast numbers of compounds for bioactivity of all types, which information can be made available for future drug selection and will greatly reduce the time and expense of such testing.
SUMMARY OF THE INVENTION
The system of the invention comprises a device array of micron sized wells and connecting channels in a substrate that interfaces with a station for dispensing fluids to and collecting fluids from, the array, and for performing electro-optic measurements of material in the wells. The station is also connected to control apparatus means to control the fluid flow to the channels and wells and to collect measurement data from the substrate. The above elements are interdependent and together can perform a variety of tasks in parallel.
The individual wells of the array and their sequence can be varied depending on the synthesis or analysis to be performed. Thus the function of the arrays can be readily changed, with only the additional need to choose suitable interface means for monitoring and controlling the flow of fluids to the particular array being used and the test or synthesis to be performed.
In one embodiment the above system can be used to perform various clinical diagnostics, such as assays for DNA in parallel, using the known protocols of the polymerase chain reaction (PCR), primers and probe technology for DNA assay. In another embodiment the above system can be used for immunoassays for antibodies or antigens in parallel for screening purposes. In still other embodiments, the synthesis of a series of chemical compounds, or a series of peptides or oligonucleotides, can be performed in parallel. Each well in the array is designed so to accomplish a selected task in appropriate modules on a substrate, each module containing the number of wells required to complete each task. The wells are connected to each other, to a sample source and to a source of reagent fluids by means of connecting microchannels. This capability permits broad based clinical assays for disease not possible by sequential assay, permits improvement in statistics of broad based clinical assays such as screening of antibodies because of the parallelism, permits a reduction in costs and an improvement in the speed of testing, and permits improved patient treatments for rapidly advancing disease.
The array is formed in a suitable dielectric substrate and the channels and wells are formed therein using maskless semiconductor patterning techniques. The station and control means, such as a computer, use existing technology that includes commercially available apparatus.
The present device array uses active control to move fluids across the array, reducing the time required for synthesis and screening. Further, large biopolymers of all types can be synthesized and processed while maintaining high purity of the synthesized compounds. The present microlaboratory arrays may be fully automated, enabling the rapid transfer of samples, precursors and other movement of fluids into the array, from one well to another well, and to enable the measurement of assays and the complete control of processing parameters such as temperature control.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1A is an exploded schematic diagram of the parts of the system of the invention adapted for performing clinical assays.
FIG. 1B is a top view of a substrate of the invention illustrating a single module formed therein.
FIG. 2 is an exploded top view of an illustrative module of the invention.
FIG. 3 is an exploded cross sectional view of the optical transmission and detection system of the invention.
FIG. 4A is a cross sectional view of a well embodiment of a microlaboratory disc of the invention.
FIG. 4B is a cross sectional view of another well embodiment of a microlaboratory disc of the invention.
FIG. 5A is a cross sectional view of a portion of a module of a microlaboratory disc illustrating devices in typical wells.
FIG. 5B is a cross sectional view of a portion of a module of a microlaboratory disc covered with a cover plate.
FIG. 6A is a cross sectional view of a microlaboratory disc illustrating additional wells having preformed devices therein together with an optical system interface.
FIGS. 6B and 6C illustrate a valve situate in a channel adjacent to a well in the open and closed positions respectively.
FIG. 7A is an exploded schematic view of another embodiment of the present invention adapted to perform immunological assays.
FIG. 7B is a top view illustrating a module on the microlaboratory disc of FIG. 7A.
FIG. 7C is a cross sectional view of a control means for moving fluids in the channels and from one well to another.
FIG. 8 is a schematic view of another embodiment of a microlaboratory array suitable for carrying out the parallel synthesis of proteins and oligonucleotides.
FIG. 9 is a schematic view illustrating a modified station for the system of FIG. 8.
FIG. 10 is a schematic view of a further embodiment of a microlaboratory array suitable for carrying out the synthesis of a large number of small molecules in parallel.
FIGS. 11A, 11B and 11C are cross sectional views illustrating the steps needed to form cross over channels in the substrate.
FIG. 11D is a top view of a cross-over channel in the substrate.
FIG. 12 is a top view of a channel "gate" electrode to control flow in a channel by electro-osmosis.
DETAILED DESCRIPTION OF THE INVENTION
The invention will be first described by reference to FIG. 1A, which illustrates the parts of an illustrative system of the invention configured to perform DNA screening diagnostics.
The system of FIG. 1A includes a computer 10, electrically connected via line 11 to peripheral apparatus, such as a modem or printer 12, which computer 10 is programmed to give instructions to a microlaboratory disc 14 and to record test results obtained therefrom. The computer 10 is electrically connected to a station 16 via line 15. The station 16 includes a microlaboratory disc support 18, support tubing 20 for loading test materials and reagents onto the microlaboratory disc 14, pumps 22 for moving fluids to particular destinations on the disk 14, one or more light sources 24, an optical fiber 25 and one or more light detectors 26. The optical fiber 25 is operative to transmit light from the light source 24 to the detector 26. One or more containers 28 for waste fluids and the like are also housed in the station 16.
A small volume of a fluid to be tested, such as a whole blood or other DNA-containing fluid sample, is loaded into the system via a loading system 30. The system 30 may house one or more capillary tubes 32, illustrated in FIG. 3, containing a sample which is connected to a loading capillary channel 34 etched into the surface of the microlaboratory disc 14. The loading capillary tube 32 is inserted into the capillary loading channel 34 horizontally. The sample is moved into the capillary loading channel 34 and the fluid sample is then moved to a first well 36 on the disc 14. Alternately, a loading channel 50 for vertical insertion into the loading channel 34 can also be used to load the sample. FIG. 1B and FIG. 2 illustrate a particular module comprising a plurality of wells 36, 40, 42 and 44 connected by a channel 38, shown by a dashed line, on a microlaboratory disc 14 of the invention. Each module is connected to a well 46 that collects excess or waste fluids from the respective module. These waste fluids are collected and moved to the waste containers 28 in the station 16.
The sample is treated sequentially in a series of wells including first well 36. For example, in the first well 36 the whole blood sample is transferred from the capillary loading channel 34, filtered and lysed to separate the white and red corpuscles, and the DNA is isolated from the white blood cells. The DNA sample is then moved out of the first well 36 through a connecting channel 38 that connects all of the wells of a single module, and into a second well 40. In the second well 40 the DNA is separated into single strands and amplified using the well known PCR method. The treated sample is then moved out of the second well 40 via the connecting channel 38 and into a third well 42. In the third well 42 the DNA is assayed by known probe hybridization techniques. The DNA assay is detected and evaluated in the fourth well 44. Thus the determination of DNA in a particular blood sample is performed in a series of four wells connected by a channel. Lastly excess reagents and the like are collected in the fifth well 46 that is common to all of the modules in the microlaboratory array 14, and is transferred into the waste collection system 28 of the station 16.
The combination of a loading channel 34 or 50, the wells 36, 40, 42, 44 and 46 and the connecting channel 38 make up one module 48 on the test microlaboratory disc 14. A single module on a microlaboratory disc 14 is shown in top view in FIG. 1B within the dashed lines. As will be explained hereinbelow, a plurality of modules are formed in the microlaboratory disc 14 so that tests can be performed on a large number of the modules 48 in parallel.
The particular sequence of channels and wells of the module shown in FIGS. 1A, 1B and FIG. 2 lends itself to the detection of pathogenic bacteria in blood or other DNA-containing fluids using the DNA assay protocols of Greisen et al, see "PCR Primers and Probes for the 16S rRNA Gene of Most Species of Pathogenic Bacteria, Including Bacteria Found in Cerebrospinal Fluid" J. Clinical Microbiology 32 (2), pp 335-351 (1994). Since the disc 14 can be arranged to form a plurality of up to 1500 parallel modules, broad DNA screening can be conducted in parallel that might not be possible using a system of sequential assays. Since a large array of parallel tests can be done at the same time, the time required to obtain meaningful results is also reduced, and consequently costs are reduced. Further, the statistics of broad based screening can be improved. In addition the system of the invention provides the ability to detect mutant DNA such as is found in oncological diseases.
The station 16 includes a fiber optic assembly 25 and one or more light sources 24 and one or more detectors 26 (not shown) that address the system loading channel 34 or 50 and measures the transmittance or absorbance of material in the channel 34 or 50 and the first well 36, such as a blood or other fluid sample. The fiber optic assembly 25 can verify the presence or absence of materials in the channel 34 or 50 or the well 36, and quantify their amounts by transmitting the measurement data to the computer 10. Suitable lasers and photodetectors are available commercially. Fiber optic adaptors to support the optical fiber are commercially available. These adaptors may also include a lens for efficient transfer of light from the light source into the fiber.
Preselected substrates, designed either for modular parallel or array processing, can be placed on the substrate holder 18 in the station 16. After suitable modification of the software in the computer 10 or choice of other driving means able to monitor a particular sequence of steps for control of reagents to carry out the processes in each module of the microlaboratory 14, entirely different tests and processes can be carried out in the system of the invention. Thus the microlaboratory array 14 is individually designed for a variety of assay, measurement and synthesis tasks, and only the module configuration and the driving means needs to be changed in the system when a different task is to be performed.
A circuit of thin film transistors (not shown) can be formed on the front or back of the glass or other substrate 14 to provide power to the wells via leads and electrodes explained further hereinafter, and to connect them with the driving means such as the computer 10, so as to move liquids along the array. Pins can also be formed in the glass substrate which are addressable by logic circuits on the support 18 that are connected to the computer 10 for example. These transistors and logic circuits will also be in contact with the substrate 14 on the support 18 to provide an interface between the microlaboratory disc 14 and the computer 10.
The system loader 30 is situated outside of the station 16 and may be connected to a loading capillary tube 32, as shown in FIG. 3, suitably having an inner diameter of about 200 microns and an outer diameter of about 600-700 microns. The capillary tube 32 can be pretreated to eliminate surface adsorption of proteins and related bio materials in a known manner, for example similar to the methods disclosed by Cobb, "Electrophoretic Separations of Proteins in Capillaries with Hydrolytically Stable Surface Structures", Anal. Chem. 62, (1990) pp 2478-2483. All of the sample material is loaded into the system via the system loader 30. The system capillary tube 32 can be loaded horizontally directly into the microlaboratory disk 14 via the loading channel 34. The sample is identified, as with a bar code or other high density code affixed to the loading capillary tube 32 as by its position on the disc array, As the sample loading tube 32 is inserted into the loading channel 34, a sealant, which can be adhered to the edge of the capillary sample tube 32 or to the loading channel 34, seals the capillary tube 32 to the channel 34. Alternately, the sample capillary tube 32 can be inserted into a separate loading channel 50 vertically, which permits a smaller loading channel to be used, but the sample may enter into the connecting channel 38 through force of gravity rather than via a controlled pump feed from the pumps 22 in the station 16. This alternate configuration 50 is also shown in FIGS. 1-3.
The heart of the present system is the parallel modular microlaboratory disc 14, shown in a side view in FIG. 1A and in a top view in FIG. 1B. FIGS. 1B and 2 illustrate a single module on a microlaboratory disc 14, which is suitably about 8.5 cm in diameter.
Each module of the microlaboratory array is made up of one or more wells connected by a channel, in turn connected to the loading capillary tube. The microlaboratory disc 14 itself can be made from glass, fused silica, quartz or a silicon wafer for example, suitably about 1 millimeter thick, that is able to be finely and controllably etched using semiconductor techniques and a suitable etchant such as HF. High quality glasses such as a high melting borosilicate glass or a fused silica, will be preferred for their UV transmission properties when any of the processes or measurements carried out in the wells or channels use light based technologies. The module 48 illustrated in FIG. 1B comprises four connecting wells, but this is by way of example only, and more or fewer wells can be present depending on the tests or syntheses to be performed in each module, and the number of steps required to perform them, as will be further described hereinbelow.
The desired number of wells are etched into the microlaboratory disk sufficient to perform the sequence of steps to be used for testing or synthesis for that particular microlaboratory disc. All of the wells in each module are connected together via one or more channels. The modular design permits efficient placement of each module on the disc substrate. When only a few wells are required for each module, two modules can be formed in each radial slice of the disc (not shown), thereby doubling the number of modules that can be etched into a single microlaboratory disk 14. Thus for an 8.5 cm diameter disk, an array of 267 single modules or 534 double modules can be readily made. When the sample is inserted vertically into the loading channel 50, which takes up less area of the substrate, additional modules can be accommodated on a single microlaboratory disc, and up to 1500 modules can be formed on a single microlaboratory disk 14. Each of the modules is connected to the system loading system 30, thus permitting parallel processing in all of the modules.
Excess fluids and waste materials for all of the modules are passed into a center well 46. A plurality of wells 46 may be connected to each other by means of a common channel 47 (FIG. 1B). A sealed tubing on the back of the substrate 14 provides an exit channel for these excess fluids that can be passed into the waste container 28 in the station 16. Thus only one exit channel 47 needs to be provided for each microlaboratory array.
The wells of the microlaboratory disc 14 can be made by the following procedure. A glass substrate disc 14 is coated sequentially on both sides with a thin chromium layer and a gold film about 1000 angstroms thick in known manner, as by evaporation or chemical vapor deposition (CVD), to protect the disc from subsequent etchants. A two micron layer of a photoresist, such as Dynakem EPA of Hoechst-Celanese Corp. is spun on and the photoresist is exposed, either using a mask or using square or rectangular images, suitably using an MRS 4500 panel stepper of MRS Technology, Inc. After developing the resist to form openings therein, and baking the resist to remove the solvent, the gold layer in the openings is etched away using a standard etch of 4 grams of KI and 1 gram of iodine (I.sub.2) in 25 ml of water. The underlying chromium layer is then separately etched using an acid chromium etch, such as KTI Chrome Etch of KTI Chemicals, Inc. The glass substrate is then etched in an ultrasonic bath of HF-HNO.sub.3 -H.sub.2 O in a ratio by volume of 14:20:66. The use of this etchant in an ultrasonic bath produces vertical sidewalls for the various wells. Etching of the wells is continued until the desired depth of the well is obtained, suitably about 200-750 microns deep, depending upon the functions to be performed in the well.
The connecting channel 38, suitably about 200 microns in width and 50-100 microns deep, is then etched between the wells, when the remaining photoresist and chromium-gold layer is removed.
Fluid material may be transmitted to the various wells from the first well 36 or from the loading channel 34 by various methods. An external mechanical pumping system 22 that can deliver fluid in reproducible and accurately controlled amounts and that can maintain the purity and sterility of test liquids can be employed. The 205U multichannel cassette pump available from Watson-Marlow, Inc is a suitable pump. Alternatively, miniaturized mechanical pumps, based on microelectromechanical systems (MEMS) can be used. These miniature pumps may be internal or external to each well 36, 40, 42 and 44. Such pumps have been reported by Shoji et al, "Fabrication of a Micropump for Integrated Chemical Analyzing Systems" Electronics and Communications in Japan, Part 2, 70, pp 52-59 (1989). Other suitable pumping means to move fluids through microchannels include electrokinetic pumps as reported by Dasgupta et al, see "Electroosmosis: A Reliable Fluid Propulsion System for Flow Injection Analysis", Anal. Chem. 66, pp 1792-1798 (1994), or electrophoresis methods, which require inert metal electrodes, can also be used. In the latter case, a gold electrode can be deposited in the various wells of a module, as shown for example as metal layer 54 in the bottom of the first well 36, as shown in FIG. 4A. The electrode 54 is connected via leads 55 to a circuit or other electrical connection 56.
When large amounts of fluid need to be passed through the connecting channel 38, such as diluents, buffer solutions, rinse solutions and the like, an external mechanical pump 22 in the station 16 will be used to pass these solutions through the channel 38 into the desired well. When smaller amounts of material are required, an on-disk internal pumping system can be used for greater efficiency. Further, prepackaged chemicals sealed in plastic release containers can be deposited in the various wells for particular tests, as required.
In the case where the temperature of a particular well is to be monitored or changed, a means of heating or cooling the well is built into the well, as will be further explained below with reference to FIG. 4B.
The first well 36 in this example is the sample preparation well. A thin film of a suitable metal oxide 57, such as tin oxide or indium tin oxide, is deposited onto the well material and is connected by means of an electrically conductive metal connection 58 to the end or outer edge of the well 36. The tin oxide coating 57 serves as a heater element for the well 36. The well 36 also has a surface bimetal film 59 and leads 60, suitably made of chromel-alumel alloys, forming a thermocouple to measure the temperature in the well when a source of current is applied to the tin oxide coating 57 and to the leads 58. A voltage applied to the well 36 via electrodes 56 deposited on the backside as shown, or preferably on the frontside of the microlaboratory disc 14, regulates the temperature in the well. The amount of current applied can be regulated by the computer 10 in response to the temperature measured through the leads 60.
The first well 36 of the present module 48 also contains a blood affinity binding material, (not shown) such as Leukosorb™ available from Pall Co. and commercially available solutions to lyse the red and white blood cells of the sample and to carry the DNA from the first well 36.
Thus the devices and certain reagents needed for each well will be preformed and loaded into the well or directly pumped into the well from a common source. Fluids can be preloaded into the well either from a reservoir in the station 16 leading to the loading capillary tube 32 connected to the microlaboratory disc 14, or a reservoir and channel into the well may be formed adjacent to the well in which the fluids will be used.
Additional devices can be built into the wells. For example, a means of stirring reactants can also be built into a well using alternating fields. For example, two or more electrodes can be evaporated into each side of a well and connected to external leads, in turn connected to a source of alternating current. The alternating fields will provide reversible magnetic fields to move paramagnetic particles in the wells and to cause, as well, fluid movement in the well.
As shown in FIG. 5A, paramagnetic beads 61 are deposited in the second well 40 of the present module 48, to bind DNA material and to move the DNA to the succeeding wells for amplification, detection and assay. These beads are commercially available for PCR protocols from Bang Laboratories of Carmel, Ind. for example. The well 40 is also connected by means of leads 66 to the electrodes 56.
When all of the wells have been prepared and loaded, a glass cover plate 63 is affixed to the microlaboratory disc 14, as shown in FIG. 5B, to complete a capillary structure for the connecting channel 38 and to ensure that fluids in the wells do not evaporate. The cover plate 63 can be made of the same or different material as the microlaboratory disc, but the thermal coefficient of expansion of the cover plate 63 and the material used to make the microlaboratory disc 14 must be similar. The sealing temperature required to seal the cover plate 63 to the disc 14 must also be below the flow temperature of the disk material to prevent distortion of the etched channels and wells. The use of electric fields to seal the cover plate to the disk is suitable because sealing will take place at a lower temperature than the flow temperature, e.g., about 700 less, which is well below the flow temperature of silicon, about 1400 from Corning Glass Co., for example.
The invention will be further explained in terms of examples that describe different modules for performing different processes, such as assays and syntheses, simultaneously and in parallel. However, the invention is not meant to be limited to the details described therein and additional processes and syntheses can be readily performed by appropriate changes to the number of wells in a module, the devices formed in or adjacent to the wells, the number and type of devices needed to pass fluids into and out of the wells, the number and type of processing-type devices built onto the disc other than the modules, and the like.
EXAMPLE 1 DNA ANALYSIS
The sample fluid is passed into the loading channel 34 or the loading channel 50 as explained above. The sample then moves by application of an electric field or is moved by a pump 22 into the first well 36 through the channel 38, where the separation of the sample, e.g., filtration, lysation and DNA separation, takes place. The first well 36 is fitted with a means of heating and temperature control, as shown in more detail in FIG. 4. A layer of tin oxide 57 is first deposited in the well 36 by CVD. A bilayer film 59 is deposited over the tin oxide film 57 in the well 36, and a metal connection 60 is deposited along a sidewall of the well. Electrodes 56 and 60 are formed on the backside of the microlaboratory disc 14, and leads 58 and 60 connect the thermocouple 59 to the external contacts 56. The current in the leads 58 and the voltage from the leads 60 are monitored and controlled by the computer 10.
The well 36 is also preloaded or post loaded with a blood affinity binding material such as Leukosorb™ media from Pall BioSupport Div. Other commercially available materials can also be used as desired for the same purpose. The amount of Leukosorb B employed depends on the area in the first well 36. The Leukosorb B filters the blood cells from the blood serum sample. A known buffer solution is then passed into the first well 36 by means of the channel 38 in an amount sufficient to assist in lysing and washing the red corpuscles in the sample. A white corpuscle lysis buffer solution, for example a solution of 50 millimoles of KCl, 10 millimoles of Tris HCl having a pH of 8.3, 2.5 millimoles of MgCl.sub.2, 0.45% Nonidet P40 and 60 ml of Proteinase K, is then passed into the first well 36 via the channel 38 in an amount sufficient to lyse the white corpuscles. The first well 36 is then heated to 55 minutes to cause the desired reaction. The cell was then heated to 100 following known procedures.
Because of the high temperatures required in the last two steps, a significant vapor pressure may develop in the first well 36, causing a back pressure in both directions--back toward the sample loading channel 34 and forward to the succeeding second well 40. Thus preformed valves 62 and 63 as shown in FIG. 6A, formed of bimetallic materials as described by Jerman et al, "Understanding Microvalve Technology", Sensors, September 1994 pp 26-36 are preloaded into the channel 38. These materials have a thermal expansion mismatch. When the temperature in the well 36 is low, the ball valve 62 is in its normal position permitting free flow of fluids into the well 36, see the arrow shown in FIG. 6B. As the temperature in the well 36 increases, the ball valve 62 moves to a cooler position, as shown in FIG. 6C, blocking the channel 38 and isolating the well 36 from the channel 38, thereby preventing fluids from passing into and out of the first well 36. By proper placement of the well heater 57, the temperature gradient from the heated well 36 will be sufficient to open and close the valves 62, 63, thus eliminating the need for separate electrical, thermal or mechanical control of the valves 62, 63.
However, other means may be employed as desired for closer control of the temperature and pressure in the well 36. A simple design comprises a small micron size sphere 64, such as one made of quartz or polytetrafluoroethylene polymer for example, which may be confined in the channel 38 to act as a conventional check valve, i.e., to prevent backward flow into the channel 38. However, there is no check on the flow forward into the succeeding well 42 with this design, which may be disadvantageous for certain applications and combinations of sequential wells. This check valve 64 can be implemented as an insulating or magnetic sphere, and by application of externally applied electrostatic or magnetic fields, cause the valve to open or close. Such a design will permit closure of the ball valve 64 on demand, permitting control of liquids both forward and backward in the channel 38. Such a design may be particularly advantageous when a synthesis procedure is carried out on the microlaboratory disc 14.
Still referring to FIG. 6A, the prepared and treated blood sample is then transferred to the second well 40 for PCR amplification of the obtained DNA sample from the first well 36. This well 40 contains a layer of paramagnetic beads 61 to bind with the DNA material moved into the well 40. A minimum of about 10 nanograms of DNA are required for this assay. The amount actually in the well 40 can be determined by the electrooptic light source 24 and detector 26 located in the station 16. An optical fiber 25 of the light source 24 is connected to the well 40, and can be an optical fiber 25 of 200, 400 or 600 micron diameter to provide 260 nm radiation for the detection of DNA in this example. Optical fibers transmitting at 250-260 nm are commercially available. The optical fiber 25 of FIG. 6A which is connected to the detector 26 collects and transmits the light measured in the well 40 to an ultraviolet sensitive silicon photodetector 26 having good stability. Suitable detectors include thermoelectrically cooled UV enhanced silicon photodetectors, or miniaturized UV sensitive photomultipliers which are also commercially available. The photomultiplier-type detector has greater sensitivity. The absorbance of DNA is known and is set forth in the Table below.
TABLE______________________________________ Absorbance Concentration,Species at 260 nm mg/ml______________________________________Double stranded DNA 1 50Single stranded DNA 1 33Single stranded RNA 1 40______________________________________
A well known means of assaying DNA is the hybridization technique. The third well 42 is used for this purpose. The well 42 will be fitted by hybridization probes which are unique to the source of DNA and its diagnostic scope. The desired probes may be directly synthesized in the well 42 or commercial sources can be used.
The method most suitable for the microlaboratory array disc 14 for assaying DNA is the use of a non-radioactive tag, which can contain a fluorescent dye, for example for the Phycobiliprotein, or other class of protein. These materials absorb light above 600 nm. A compact solid state laser 24 emitting in the 600-650 nm range situate in the station 16 can be used to produce fluorescence in the tag. The probe in this example will emit above the exciting wavelength of 600 nm, i.e., in the 600-800 nm range. The Phycobiliprotein fluorescent tag agents are commercially available, e.g., Cy.sub.5 ™ from Jackson Immuno-Research Labs. Inc of West Grove Pa. The fluorescence will be detected by means of the detector 26 also in the station 16. A filter 68 will also be inserted between the photomultiplier photodetector 26 and the laser 24 as shown in FIG. 6 to block the laser radiation.
A suitable detector for the fluorescence emitted by the fluorescent tag is one having high sensitivity and optimum long term stability. Other commercially available means for detection of antibodies other than that described above can also be employed. For example, enzymes that form highly colored products, resulting in detection having excellent sensitivity, or chemiluminescent compounds can be employed and detected optically. Radioisotopes can also be used, but their use is being discouraged to prevent adverse effects on the operator of the tests, and they present disposal problems. The light transmission detection system itself is also located in the station 16.
EXAMPLE 2 IMMUNOLOGICAL ASSAY
A second example illustrating the design and utility of a microlaboratory disc 114 is shown in FIGS. 7A and 7B and is one suitable for carrying out a plurality of immunological assays, also in parallel. The station 16, sample loading channel 134, and plurality of wells 136, 140, 142 and 144 connected by a channel 138 are similar to those of Example 1, but the materials and processes carried out in the wells, and the number of wells required, are different.
To carry out an immunological assay, a blood sample or other fluid sample of about 100 nanoliters is filtered to obtain a material having sufficient antibodies so that an assay can be determined using standard methods for detection of select antibodies. The microlaboratory disc 114 is able to process 200-1000 samples in parallel.
The initial transfer of a sample to the microlaboratory array 114 is the same as for Example 1. The first well 136 is loaded with preselected bound antibodies on the cell wall, and, by transfer of appropriate reagents and fluid flow control into each well 136 of the module 148, assays can be performed with that antibody. The flow of reagents and solvent will be controlled by the station 16, and the optical detection system 24, 25 and 26 will be set up for transmittance (absorption) measurements.
A series of different antibodies can be placed in additional wells 140, 142, 144 and 146 for sequential testing for various antibodies in successive wells, as shown in FIG. 7B. The number of wells required will be determined by the number of appropriate reagents and the number of antibodies to be tested.
A control means 171 to control the fluid flow of reagents and solvents will be enabled by element 162, which is a switch or valve that controls the flow of fluid into the channel 138 and into the first well 136. For example, a magnetic sphere can form a ball valve 162 by activation of an electric field by means of the computer 10.
As shown in FIG. 7C, a ball valve 162 is fitted into the channel 138 on both sides of the well 136. A source of current 170 is placed adjacent the channel 138 to control the flow into or out of the well 136, and the backside of the microlaboratory disc 114 will have a lead 172 that connects to the driving method employed, such as the computer 10.
EXAMPLE 3 SYNTHESIS OF PROTEINS OR OLIGONUCLEOTIDES
This example, shown in FIG. 8, illustrates a microlaboratory disc 214 that has a modular design that permits the synthesis of a large array of proteins or oligonucleotides in parallel. Such synthesis is a great time saver for drug testing for example, when a whole series of related compounds can be synthesized in each well of an array, and then tested for biologic activity.
For example, the synthesis of solid phase oligonucleotides in a well has been described by Hayakawa et al, "The Allylic Protection Method in Solid-Phase Oligonucleotide Synthesis. An Efficient Preparation of Solid-Anchored DNA Oligomers", J. Am. Chem. Soc., Vol 112, No. 5, 1990 pp 1691-1696, in a sequence of eight steps:
Step 1: washing the well with acetonitrile (CH.sub.3 CN)
Step 2: detritylation with 3% Cl.sub.3 CCOOH - CH.sub.2 Cl.sub.2
Step 3: washing the well with acetonitrile
Step 4: adding a coupling agent such as 0.1M phosphoramidite-CH.sub.3 CN and 0.5M (4-nitrophenyl)tetrazole-CH.sub.3 CN-THF (tetrahydrofuran)
Step 5: washing the well with acetonitrile
Step 6: capping with Ac.sub.2 O-2,6-lutidine-THF (1:1:8) and 6.5% 4-(dimethylamino)pyridine (DMAP)-THF
Step 7: oxidizing with 1.1M t-C.sub.4 H.sub.9 OOH-CH.sub.2 Cl.sub.2
Step 8: washing the well with acetonitrile to remove excess acid.
After the above 8 steps have been carried out in a reaction well 237 using different protected monomers sequentially to build up lengths of oligomers as desired, additional reagents or solvents can be used to remove protective groups used for synthesis prior to disassociating the synthesized oligomers from their support. The various oligomers in each well can then be prepared for screening. A screening cell 274 can also be built into the well 236 as shown in FIG. 8.
In this design, as shown in FIG. 8, a plurality of modules or wells 236 are connected by means of various channels, and a complete synthesis of different compounds will be carried out in a single well 236. The additional features of this microlaboratory 214 design are in the array design which permits controllable and sequential delivery of various reagents and solvents to each of the wells in parallel. The reagents and solvents can be stored in reservoirs 276, 278, 280 and 282 built into the microlaboratory array, or they may be delivered from reservoirs external to the microlaboratory array, for example in the station 16, as desired.
FIG. 8 illustrates a suitable design for a microlaboratory array wherein reservoirs 276, 278, 280, 282 for reagents and solvents are included in the substrate; and FIG. 9 is a partial schematic view of a system for synthesis wherein reservoirs 276, 279, 280 and 282 are added to the station 16, each connected to a fluid pump 22 for delivery to the wells of each module.
Each well in this array has a plurality of horizontal channels 238, 239, 241, 243, 245 entering and exiting each well 236, and a plurality of vertical channels 248, 250, 252 and 254, each of which leads to a different reservoir. The reagents and solvents move along the channels by means of gating electrodes, as shown in FIG. 7C, that move the fluid along the channels.
As shown in FIG. 8, reagents are delivered in parallel from the different reservoirs 276, 278, 280 and 282 into channels 238, 239, 241, 243 respectively. Each of these channels has a built in gating electrode 162 to monitor the flow of fluids from the different reservoirs into the wells 236 as required. In this embodiment, since all of the synthesis reactions take place in a single well 236, each well 236 is placed in an array and one or more channels lead into and out of each well 236 for delivery of reagents in parallel or serially. Thus instead of a modular design, when sequential wells are used for the various steps of the process being carried out, an array of like wells 236 is used but a different chemical synthesis is carried out in each well. The overall design is no longer a plurality of modules, but an array of wells, and hundreds of compounds can be synthesized on a single microlaboratory substrate 214.
After all the synthetic steps are completed, the syntheses can be monitored or screening can be conducted by passing a sample into a screening cell 274 which can be built into the well 236.
This type of array can be used to synthesize a large number of oligomers and peptides which follow a repetitive sequence of steps as above.
EXAMPLE 4 SYNTHESIS OF SMALL MOLECULES
This microlaboratory array of this example 314 is also designed to produce an array of small molecules, such as a plurality of different alkyl compounds. Since such an array depends on the delivery of a different starting material for each compound, e.g., methyl-substituted, ethyl-substituted, n-propyl-substituted, iso-propyl substituted compounds and the like, a large array of starting material reservoirs or supply sources will be needed so that a different starting material will be delivered to each well. The reactants and solvents and reaction conditions, e.g., heating, will be delivered as required, see Examples 1 and 2.
For example, the synthesis of an array of 1,4-benzodiazeprine compounds can be carried out as follows:
Step a): bind the starting material 4-[4-benzoyl-6-chloro -2-fluorenylmethoxy carbonylaminobenzoyloxy-methyl]phenoxyacetic acid onto aminomethyl resin or its equivalent as a coating material on the channel surfaces;
Step b): remove the 9-fluorenyl methoxy carbonyl (FMOC) protective group from the bound material using piperidine in DMF, supplied from station reservoir 376 into the wells 338;
Step c): couple an amino acid, alpha-N-FMOC-amino acid (fluoride) from a second reservoir 378 in the well 338;
Step d): remove the FMOC protective group by moving piperidine in DMF through the wells 338;
Step e): forming a cyclic benzodiazepine derivative with 5% acetic acid in DMF from a third reservoir 380 in wells 340;
Step f): alkylate with a lithium salt in DMF from a station reservoir 382 in wells 342 that are fitted with a control for pumps and switches, monitored by the computer 10, to deliver different alkylating agents to the microlaboratory array 314 selectively, as shown in FIG. 10. Thus the "reservoir" for the alkylating agent is in reality a source of a whole series of alkylating agents that can be delivered selectively to a particular well in the array. The fluid delivery to the wells can be controlled by a control means 171 as shown in FIG. 7C. In this manner, a different compound is made in each well. However, since each compound requires several steps for synthesis of the various compounds, several wells may be employed to synthesize each of the compounds and this microlaboratory disc 314 may comprise a plurality of modules as well.
Another feature of the present invention is the fabrication of cross-over channels that permit high density arrangements of wells/modules in an array that can be serviced from more than one channel either to transmit fluids into the well, out of the well, or to transmit the material being treated to a succeeding well. Such cross over channels can be formed in the following manner. Referring to FIG. 11A, a substrate 314 is coated on both sides with a first chromium-gold layer 310A and 310B and a photoresist layer 312A and 312B as described above. The photoresist layer 312A is exposed and developed to form openings 313 for a first channel and the chromium layer 312A is etched away in the opening 313. The glass substrate 314 is then etched through to the chromium-gold layer 310B forming openings 315. The photoresist layers 312A and 312B are re-exposed and developed to form a second pair of openings 316 and 317 on each side of the glass substrate 314. However, the second opening 316 in the layer 312A is perpendicular to the opening 317 in the layer 312B, which is parallel to the openings 315 made originally. The opening 317 is formed adjacent to the openings 315 already formed in the glass substrate 314, as shown in FIG. 11B. The glass substrate is next etched to open a passage between the openings 315 and 317, thereby forming a continuous channel that extends through the glass substrate 314 and across beneath the second perpendicular channel 316 as shown in FIG. 11C. A cover plate 318 will be bonded to both sides of the substrate 314 to enclose the cross-over channels 315-317-315 and 316 on both sides of the substrate 314 and to complete the substrate having crossing but non-intersecting channels, as shown in FIG. 11D.
In order to move materials from the reservoirs into each well of the array, the material from the reservoir can be injected into one or more the channels 316. The material in each channel moves along the channel 316 via capillary action. However, since one or more of the reactions may require more or less time depending on the amount of material employed, or to compensate for faster or slower movement of certain materials through the channels, the material flow in the channels preferably can be controlled by means of a drain electrode deposited in each well, and in each reservoir and in the channel leading from the reservoir to the respective well. By creating a negative charge at the well, the flow along the channel will be stopped, thereby permitting control of reagent feed into each well. This is shown in FIG. 12 which is a top view which shows a drain electrode 440 deposited in the well 436, in a channel 438, and in the reservoir 442.
A desired microlaboratory array can be designed to carry out a wide variety of tests and syntheses rapidly, reliably, inexpensively and in parallel, greatly reducing costs. Further, because of the integration of the microlaboratory array and means of regulating, measuring and recording information, records of tests and screening data are reliably generated and stored. Since genetic screening may become the blood tests of the future, the ability to perform DNA testing rapidly, reliably and at low cost, will be highly advantageous.
Thus although the present invention has been described in terms of particular examples, the invention is not meant to be limited to the details given above. One skilled in the art can readily substitute different mechanical or electrical means of transferring fluids through the channels and wells, of substituting various bonding agents, starting materials and reagents to perform different assays and syntheses, and to form the wells, channels and devices in the channels and wells by alternate methods. For example, integrated circuits can also be employed to move fluids and monitor and measure wells of the arrays using conventional semiconductor techniques and materials. Semiconductor technology can also be used to form leads, electrodes and the like. Thus the invention is only to be limited by the scope of the following claims.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3494723 *||Dec 5, 1967||Feb 10, 1970||Gray Ind Inc||Method and apparatus for controlling microorganisms and enzymes|
|US3615241 *||Feb 27, 1970||Oct 26, 1971||Nasa||Firefly pump-metering system|
|US4276048 *||Jun 14, 1979||Jun 30, 1981||Dynatech Ag||Miniature reaction container and a method and apparatus for introducing micro volumes of liquid to such a container|
|US4385115 *||Oct 22, 1980||May 24, 1983||Hoffmann-La Roche Inc.||Diagnostics testing devices and processes|
|US4683914 *||Oct 4, 1984||Aug 4, 1987||Brisland Michael J||Slide valve|
|US4753775 *||Apr 12, 1985||Jun 28, 1988||E. I. Du Pont De Nemours And Company||Rapid assay processor|
|US4756884 *||Jul 1, 1986||Jul 12, 1988||Biotrack, Inc.||Capillary flow device|
|US4891120 *||Jun 8, 1987||Jan 2, 1990||Sethi Rajinder S||Chromatographic separation device|
|US4908112 *||Jun 16, 1988||Mar 13, 1990||E. I. Du Pont De Nemours & Co.||Silicon semiconductor wafer for analyzing micronic biological samples|
|US4948961 *||Apr 5, 1988||Aug 14, 1990||Biotrack, Inc.||Capillary flow device|
|US4960486 *||Feb 23, 1990||Oct 2, 1990||Brigham Young University||Method of manufacturing radiation detector window structure|
|US4963498 *||Jan 15, 1988||Oct 16, 1990||Biotrack||Capillary flow device|
|US4999283 *||Aug 18, 1989||Mar 12, 1991||University Of Kentucky Research Foundation||Method for x and y spermatozoa separation|
|US4999284 *||Apr 6, 1988||Mar 12, 1991||E. I. Du Pont De Nemours And Company||Enzymatically amplified piezoelectric specific binding assay|
|US4999286 *||Dec 23, 1986||Mar 12, 1991||E. I. Du Pont De Nemours And Company||Sulfate reducing bacteria determination and control|
|US5000817 *||Jan 19, 1988||Mar 19, 1991||Aine Harry E||Batch method of making miniature structures assembled in wafer form|
|US5001048 *||Jun 5, 1987||Mar 19, 1991||Aurthur D. Little, Inc.||Electrical biosensor containing a biological receptor immobilized and stabilized in a protein film|
|US5006749 *||Oct 3, 1989||Apr 9, 1991||Regents Of The University Of California||Method and apparatus for using ultrasonic energy for moving microminiature elements|
|US5063081 *||Aug 15, 1990||Nov 5, 1991||I-Stat Corporation||Method of manufacturing a plurality of uniform microfabricated sensing devices having an immobilized ligand receptor|
|US5066938 *||Oct 11, 1990||Nov 19, 1991||Kabushiki Kaisha Kobe Seiko Sho||Diamond film thermistor|
|US5073029 *||Feb 16, 1990||Dec 17, 1991||Eqm Research, Inc.||Multisource device for photometric analysis and associated chromogens|
|US5118384 *||Dec 10, 1991||Jun 2, 1992||International Business Machines Corporation||Reactive ion etching buffer mask|
|US5129262 *||Jan 18, 1990||Jul 14, 1992||Regents Of The University Of California||Plate-mode ultrasonic sensor|
|US5140161 *||Jul 23, 1991||Aug 18, 1992||Biotrack||Capillary flow device|
|US5141868 *||Nov 27, 1989||Aug 25, 1992||Internationale Octrooi Maatschappij "Octropa" Bv||Device for use in chemical test procedures|
|US5143854 *||Mar 7, 1990||Sep 1, 1992||Affymax Technologies N.V.||Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof|
|US5144139 *||Jul 19, 1991||Sep 1, 1992||Biotrack, Inc.||Capillary flow device|
|US5147607 *||Nov 29, 1990||Sep 15, 1992||Mochida Pharmaceutical Co., Ltd.||Reaction vessel with a rocking base|
|US5156810 *||Jun 15, 1989||Oct 20, 1992||Biocircuits Corporation||Biosensors employing electrical, optical and mechanical signals|
|US5164598 *||Feb 5, 1991||Nov 17, 1992||Biotrack||Capillary flow device|
|US5176203 *||Jul 31, 1990||Jan 5, 1993||Societe De Conseils De Recherches Et D'applications Scientifiques||Apparatus for repeated automatic execution of a thermal cycle for treatment of samples|
|US5178190 *||Nov 29, 1991||Jan 12, 1993||Robert Bosch Gmbh||Microvalve|
|US5188963 *||Nov 17, 1989||Feb 23, 1993||Gene Tec Corporation||Device for processing biological specimens for analysis of nucleic acids|
|US5189914 *||Nov 15, 1991||Mar 2, 1993||The Regents Of The University Of California||Plate-mode ultrasonic sensor|
|US5194133 *||May 3, 1991||Mar 16, 1993||The General Electric Company, P.L.C.||Sensor devices|
|US5200051 *||Nov 7, 1989||Apr 6, 1993||I-Stat Corporation||Wholly microfabricated biosensors and process for the manufacture and use thereof|
|US5204525 *||Jul 19, 1991||Apr 20, 1993||Biotrack||Capillary flow device|
|US5212988 *||Oct 10, 1991||May 25, 1993||The Reagents Of The University Of California||Plate-mode ultrasonic structure including a gel|
|US5220189 *||Jul 6, 1983||Jun 15, 1993||Honeywell Inc.||Micromechanical thermoelectric sensor element|
|US5229297 *||Oct 15, 1992||Jul 20, 1993||Eastman Kodak Company||Containment cuvette for PCR and method of use|
|US5230864 *||Apr 10, 1991||Jul 27, 1993||Eastman Kodak Company||Gravity assisted collection device|
|US5238853 *||Sep 11, 1991||Aug 24, 1993||Instrumentation Laboratory S.R.L.||Process and apparatus for the electrochemical determination of oxygen in a blood gas analyzer|
|US5241363 *||Feb 28, 1992||Aug 31, 1993||General Atomics||Micropipette adaptor with temperature control for PCR amplification|
|US5250263 *||Oct 30, 1991||Oct 5, 1993||Ciba-Geigy Corporation||Apparatus for processing or preparing liquid samples for chemical analysis|
|US5252743 *||Nov 13, 1990||Oct 12, 1993||Affymax Technologies N.V.||Spatially-addressable immobilization of anti-ligands on surfaces|
|US5262127 *||Feb 12, 1992||Nov 16, 1993||The Regents Of The University Of Michigan||Solid state chemical micro-reservoirs|
|US5288463 *||Apr 2, 1993||Feb 22, 1994||Eastman Kodak Company||Positive flow control in an unvented container|
|US5296114 *||Nov 30, 1992||Mar 22, 1994||Ciba-Geigy Corporation||Electrophoretic separating device and electrophoretic separating method|
|US5296375 *||May 1, 1992||Mar 22, 1994||Trustees Of The University Of Pennsylvania||Mesoscale sperm handling devices|
|US5304487 *||May 1, 1992||Apr 19, 1994||Trustees Of The University Of Pennsylvania||Fluid handling in mesoscale analytical devices|
|US5312590 *||Apr 24, 1989||May 17, 1994||National University Of Singapore||Amperometric sensor for single and multicomponent analysis|
|US5322258 *||Apr 19, 1990||Jun 21, 1994||Messerschmitt-Bolkow-Blohm Gmbh||Micromechanical actuator|
|US5324483 *||Feb 2, 1993||Jun 28, 1994||Warner-Lambert Company||Apparatus for multiple simultaneous synthesis|
|US5324633 *||Nov 22, 1991||Jun 28, 1994||Affymax Technologies N.V.||Method and apparatus for measuring binding affinity|
|US5359115 *||Sep 11, 1992||Oct 25, 1994||Affymax Technologies, N.V.||Methods for the synthesis of phosphonate esters|
|US5384261 *||Nov 22, 1991||Jan 24, 1995||Affymax Technologies N.V.||Very large scale immobilized polymer synthesis using mechanically directed flow paths|
|US5412087 *||Apr 24, 1992||May 2, 1995||Affymax Technologies N.V.||Spatially-addressable immobilization of oligonucleotides and other biological polymers on surfaces|
|US5420328 *||Sep 9, 1993||May 30, 1995||Affymax Technologies, N.V.||Methods for the synthesis of phosphonate esters|
|US5424186 *||Dec 6, 1991||Jun 13, 1995||Affymax Technologies N.V.||Very large scale immobilized polymer synthesis|
|US5427946 *||Jan 21, 1994||Jun 27, 1995||Trustees Of The University Of Pennsylvania||Mesoscale sperm handling devices|
|US5463564 *||Sep 16, 1994||Oct 31, 1995||3-Dimensional Pharmaceuticals, Inc.||System and method of automatically generating chemical compounds with desired properties|
|US5480614 *||Mar 16, 1994||Jan 2, 1996||Hitachi, Ltd.||Micro-reactor device for minute sample analysis|
|DE3811052C1 *||Mar 31, 1988||Aug 24, 1989||Messerschmitt-Boelkow-Blohm Gmbh, 8012 Ottobrunn, De||Title not available|
|EP0198413A2 *||Apr 9, 1986||Oct 22, 1986||E.I. Du Pont De Nemours And Company||Rapid assay processor|
|EP0402995A2 *||Jun 7, 1990||Dec 19, 1990||Johnson & Johnson Clinical Diagnostics, Inc.||Temperature control device and reaction vessel|
|EP0430248A2 *||Nov 29, 1990||Jun 5, 1991||Mochida Pharmaceutical Co., Ltd.||Reaction vessel|
|EP0483117A2 *||Jul 24, 1986||Apr 29, 1992||Boehringer Mannheim Corporation||Capillary flow device|
|GB2248840A *|| ||Title not available|
|WO1990009596A1 *||Feb 9, 1990||Aug 23, 1990||David Roger Vale||Testing of liquids|
|WO1991016966A1 *||May 8, 1991||Nov 14, 1991||Pharmacia Biosensor Ab||Microfluidic structure and process for its manufacture|
|WO1992010092A1 *||Nov 20, 1991||Jun 7, 1992||Affymax Tech Nv||Very large scale immobilized polymer synthesis|
|WO1993006121A1 *||Sep 16, 1992||Apr 1, 1993||Affymax Tech Nv||Method of synthesizing diverse collections of oligomers|
|WO1993022058A1 *||Apr 29, 1993||Nov 11, 1993||Univ Pennsylvania||Polynucleotide amplification analysis using a microfabricated device|
|WO1994005414A1 *||Aug 31, 1993||Mar 17, 1994||Univ California||Microfabricated reactor|
|WO1994010128A1 *||Oct 22, 1993||May 11, 1994||Affymax Tech Nv||Novel photoreactive protecting groups|
|WO1995012608A1 *||Nov 2, 1994||May 11, 1995||Affymax Tech Nv||Synthesizing and screening molecular diversity|
|1|| *||Angell, et al., Silicon Micromechanical Devices, Scientific American 248:44 55, 1983.|
|2||Angell, et al., Silicon Micromechanical Devices, Scientific American 248:44-55, 1983.|
|3|| *||Avila Whitesides, Catalytic Activity of Native Enzymes During Capillary Electrophoresis: An Enzymatic Microreactor, J. Org. Chem. 58:5508 5512, 1993.|
|4||Avila Whitesides, Catalytic Activity of Native Enzymes During Capillary Electrophoresis: An Enzymatic Microreactor, J. Org. Chem. 58:5508-5512, 1993.|
|5|| *||Bao and Regnier, Ultramicro Enzyme Assays in a Capillary Electrophoretic System, J. Chrom. 608:217 224, 1992.|
|6||Bao and Regnier, Ultramicro Enzyme Assays in a Capillary Electrophoretic System, J. Chrom. 608:217-224, 1992.|
|7|| *||Bart, et al., Microfabricated Electrohydrodynamic Pumps, Sensors and Actuators, A21 A23:193 197, 1990.|
|8||Bart, et al., Microfabricated Electrohydrodynamic Pumps, Sensors and Actuators, A21-A23:193-197, 1990.|
|9||Cobb et al, "Electrophoretic Separations . . . ", Anal. Chem. vol. 62, 1990, pp. 2478-2483 month not available.|
|10|| *||Cobb et al, Electrophoretic Separations . . . , Anal. Chem. vol. 62, 1990, pp. 2478 2483 month not available.|
|11||Dasgupta et al, "Electroosmosis: A Reliable Fluid . . . ", Anal. Chem. vol. 66, No. 11, Jun. 1, 1994, pp. 1792-1798.|
|12|| *||Dasgupta et al, Electroosmosis: A Reliable Fluid . . . , Anal. Chem. vol. 66, No. 11, Jun. 1, 1994, pp. 1792 1798.|
|13|| *||Dialog Search, May 19, 1994.|
|14|| *||Excerpt for Chemical & Engineering News, Microfabricated Device is Chemistry Lab on a Chip, Dec. 12, 1991.|
|15||Fan et al, "Micromachining of Capillary . . . " Anal. Chem. vol. 66, No. 1, Jan. 1, 1994, pp. 177-184.|
|16|| *||Fan et al, Micromachining of Capillary . . . Anal. Chem. vol. 66, No. 1, Jan. 1, 1994, pp. 177 184.|
|17|| *||Fan, et al., Micromachining of Capillary Electrophoresis Injectors and Separators on Glass Chips and Evaluation of Flow at Capillary Intersections, Anal. Chem., 1994, 6:177 184.|
|18||Fan, et al., Micromachining of Capillary Electrophoresis Injectors and Separators on Glass Chips and Evaluation of Flow at Capillary Intersections, Anal. Chem., 1994, 6:177-184.|
|19||Fisher, "Microchips for Drug Compounds", New York Times, Mar. 3, 1991.|
|20|| *||Fisher, Microchips for Drug Compounds , New York Times, Mar. 3, 1991.|
|21|| *||Fisher, Microchips for Drug Compounds, New York times, Mar. 3, 1991.|
|22||Fodor et al, "Light-Directed, Spatially . . . " Science, vol. 251, Feb. 156, 1991.|
|23|| *||Fodor et al, Light Directed, Spatially . . . Science, vol. 251, Feb. 156, 1991.|
|24|| *||Fodor, ete al., Light Directed, Spatially Addressable Parallel Chemical Synthesis, Research Article, Science, vol. 251, Feb. 15, 1991, pp. 767 773.|
|25||Fodor, ete al., Light-Directed, Spatially Addressable Parallel Chemical Synthesis, Research Article, Science, vol. 251, Feb. 15, 1991, pp. 767-773.|
|26|| *||Gazette entry for Murphy, et al., Automated Capillary Scanning System, U.S. Patent No. 5,009,503, Apr. 23, 1991.|
|27|| *||Gazette entry for Semancik, et al., Temperature Controlled, Micromachined Arrays for Chemical Sensor Fabrication and Operation, U.S. Patent No. 5,345,213, Sep. 6, 1994.|
|28||Gazette entry for Semancik, et al., Temperature-Controlled, Micromachined Arrays for Chemical Sensor Fabrication and Operation, U.S. Patent No. 5,345,213, Sep. 6, 1994.|
|29|| *||Harmon, et al., Electrophoretically Mediated Microanalysis of Ethanol, J. Chrom. A, 657:429 434, 1993.|
|30||Harmon, et al., Electrophoretically Mediated Microanalysis of Ethanol, J. Chrom. A, 657:429-434, 1993.|
|31|| *||Harmon, et al., Mathematical Treatment of Electrophoretically Mediated Microanalysis, Anal. Chem. 65:2655 2662, 1993.|
|32||Harmon, et al., Mathematical Treatment of Electrophoretically Mediated Microanalysis, Anal. Chem. 65:2655-2662, 1993.|
|33|| *||Harmon, et al., Selectively in Electrophoretically Mediated Microanalysis by Control of Product Detection Time, Anal. Chem. 66:3797 3805, 1994.|
|34||Harmon, et al., Selectively in Electrophoretically Mediated Microanalysis by Control of Product Detection Time, Anal. Chem. 66:3797-3805, 1994.|
|35||Harrison et al, "Capillary Electrophoresis . . . ", Anal. Chem. vol. 64, 1992, pp. 1926-1932 Month not available.|
|36||Harrison et al, "Micromachining a Miniaturized . . . " Science, vol. 261, Aug. 13, 1993, pp. 895-897.|
|37|| *||Harrison et al, Capillary Electrophoresis . . . , Anal. Chem. vol. 64, 1992, pp. 1926 1932 Month not available.|
|38|| *||Harrison et al, Micromachining a Miniaturized . . . Science, vol. 261, Aug. 13, 1993, pp. 895 897.|
|39|| *||Harrison, et al., Capillary Electrophoresis and Sample Injection Systems Integrated on a Planar Glass Chip, Anal. Chem. 1992, 64:1926 1932.|
|40||Harrison, et al., Capillary Electrophoresis and Sample Injection Systems Integrated on a Planar Glass Chip, Anal. Chem. 1992, 64:1926-1932.|
|41|| *||Harrison, et al., Micromachining a Miniaturized Capillary Electrophoresis Based Chemical Analysis System on a Chip, Science, vol. 261, Aug. 13, 1993.|
|42||Harrison, et al., Micromachining a Miniaturized Capillary Electrophoresis-Based Chemical Analysis System on a Chip, Science, vol. 261, Aug. 13, 1993.|
|43||Hayakawa et al, "The Allylic Protection Method . . . ", J. Am. Chem. Soc., vol. 112, No. 5, 1990, pp. 1691-1696 month not available.|
|44|| *||Hayakawa et al, The Allylic Protection Method . . . , J. Am. Chem. Soc., vol. 112, No. 5, 1990, pp. 1691 1696 month not available.|
|45|| *||Howe, et al., Silicon Micromechanics; Sensors and Actuators on a Chip, IEEE Spectrum, Jul. 1990.|
|46||Jacobson et al, "Effects of Injection . . . ", Anal. Chem. vol. 66, No. 7, Apr. 1, 1994 month not available.|
|47||Jacobson et al, "High Speed Separations . . . ", Anal. Chem. vol. 66, 1994, pp. 1114-1118 month not available.|
|48|| *||Jacobson et al, Effects of Injection . . . , Anal. Chem. vol. 66, No. 7, Apr. 1, 1994 month not available.|
|49|| *||Jacobson et al, High Speed Separations . . . , Anal. Chem. vol. 66, 1994, pp. 1114 1118 month not available.|
|50|| *||Jacobson, et al., Effects of Injection Schemes and Column Geometry on the Performance of Microchip Electrophoresis Devices, Anal. Chem. 1994, 66:1107 1113.|
|51||Jacobson, et al., Effects of Injection Schemes and Column Geometry on the Performance of Microchip Electrophoresis Devices, Anal. Chem. 1994, 66:1107-1113.|
|52|| *||Jacobson, et al., High Speed Separations on a Microchip, anal. Chem. 1994, 66:1114 1118.|
|53||Jacobson, et al., High-Speed Separations on a Microchip, anal. Chem. 1994, 66:1114-1118.|
|54|| *||Jacobson, et al., Precoloun Reactions with Electro Phoretic Analysis Integrated on a Microchip, Anal. Chem. 66:4127 4132, 1994.|
|55||Jacobson, et al., Precoloun Reactions with Electro Phoretic Analysis Integrated on a Microchip, Anal. Chem. 66:4127-4132, 1994.|
|56||Jerman et al, "Understanding Microvalve Technology", Sensors, Sep. 1994, pp. 26-36.|
|57|| *||Jerman et al, Understanding Microvalve Technology , Sensors, Sep. 1994, pp. 26 36.|
|58|| *||Medynski, Synthetic Peptide Combinatorial Libraries, Bio/Technology, vol. 12, Jul. 1994.|
|59|| *||Megregany, Microelectromechanical Systems, Circuits and Devices, Jul. 1993.|
|60||Mehregany, "Microelectromechanical Systems", 1993 IEEE, Circuits & Devices, pp. 14-22 Month not available.|
|61|| *||Mehregany, Microelectromechanical Systems , 1993 IEEE, Circuits & Devices, pp. 14 22 Month not available.|
|62|| *||Melcher, Traveling Wave Induced Electroconvection, The Physics of Fluids, 9:1548 1555, 1966.|
|63||Melcher, Traveling-Wave Induced Electroconvection, The Physics of Fluids, 9:1548-1555, 1966.|
|64|| *||Patterson, et al., Electrophoretically Mediated Microanalysis of Calcium, J. Chromatog. A, 662:289 395, 1994.|
|65||Patterson, et al., Electrophoretically Mediated Microanalysis of Calcium, J. Chromatog. A, 662:289-395, 1994.|
|66||Petersen, "Silicon as a Mechanical Material", Proc. IEEE vol. 70 No. 5, May, 1982.|
|67|| *||Petersen, Silicon as a Mechanical Material , Proc. IEEE vol. 70 No. 5, May, 1982.|
|68|| *||Petersen, Silicon as a Mechanical Material, Proceedings of the IEEE, vol. 79, No. 5, May 1982.|
|69|| *||Pickard, Ion Drag Pumping. I. Theory, J. Applied Physics 34:246 250, 1963.|
|70||Pickard, Ion Drag Pumping. I. Theory, J. Applied Physics 34:246-250, 1963.|
|71|| *||Pickard, Ion Drag Pumping. II. Experiment, J. Applied Physics, 34:251 258, 1963.|
|72||Pickard, Ion Drag Pumping. II. Experiment, J. Applied Physics, 34:251-258, 1963.|
|73|| *||Richeter, et al., A Micromachined Electrohydrodynamic (EHD) Pump, Sensors and Actuators A, 29:159 168, 1992.|
|74||Richeter, et al., A Micromachined Electrohydrodynamic (EHD) Pump, Sensors and Actuators A, 29:159-168, 1992.|
|75|| *||Search Report for WO 93/22053, Micro Fabricated Detection Structures, Nov. 11, 1993.|
|76||Search Report for WO 93/22053, Micro-Fabricated Detection Structures, Nov. 11, 1993.|
|77|| *||Search Report for WO 93/22054, Analysis Based on Flow Restriction, Nov. 11, 1993.|
|78|| *||Search Report for WO 93/22421, Micro Fabricated Sperm Handling Device, Nov. 11, 1993.|
|79||Search Report for WO 93/22421, Micro-Fabricated Sperm Handling Device, Nov. 11, 1993.|
|80|| *||Search Report WO 93/22055, Fluid Handling in Micro Fabricated Analytical Devices, Nov. 11, 1993.|
|81||Search Report WO 93/22055, Fluid Handling in Micro-Fabricated Analytical Devices, Nov. 11, 1993.|
|82||Shoji et al, "Fabrication of a Micropump . . . ", Elec. & Comm in Japan, Part 2, vol. 72, No. 10, 1989, pp. 52-59 Month not available.|
|83|| *||Shoji et al, Fabrication of a Micropump . . . , Elec. & Comm in Japan, Part 2, vol. 72, No. 10, 1989, pp. 52 59 Month not available.|
|84|| *||Stuetzer, Ion Drag Pumps, J. Applied Physics, 31:136 146, 1960.|
|85||Stuetzer, Ion Drag Pumps, J. Applied Physics, 31:136-146, 1960.|
|86||The Economist, "The silver shotguns", Dec. 14, 1991.|
|87|| *||The Economist, The silver shotguns , Dec. 14, 1991.|
|88|| *||The Silver Shotguns, The Economist, Dec. 14 20, 1991.|
|89||The Silver Shotguns, The Economist, Dec. 14-20, 1991.|
|90|| *||Tracey, et al., Microfabricated Microhaemorheometer, pp. 82 84, 1991.|
|91||Tracey, et al., Microfabricated Microhaemorheometer, pp. 82-84, 1991.|
|92||Washizu et al, "Electrostatic Manipulation of DNA . . . ", IEEE Trans. vol. 26, No. 6, 1990, pp. 1165-1172 month not available.|
|93|| *||Washizu et al, Electrostatic Manipulation of DNA . . . , IEEE Trans. vol. 26, No. 6, 1990, pp. 1165 1172 month not available.|
|94|| *||Wenzel, et al., A Multisensor Employing an Ultrasonic Lamb Wave Oscillator, IEEE Transactions on Electron Devices, vol. 35, No. 5, Jun. 1988.|
|95||Wenzel, et al., A Multisensor Employing an Ultrasonic Lamb-Wave Oscillator, IEEE Transactions on Electron Devices, vol. 35, No. 5, Jun. 1988.|
|96||Wooley et al, "Ultra-high speed DNA . . . ", Proc. Natl. Acad. Sci. USA, vol. 91, No. 1994, pp. 11348-11352 month unavailable.|
|97|| *||Wooley et al, Ultra high speed DNA . . . , Proc. Natl. Acad. Sci. USA, vol. 91, No. 1994, pp. 11348 11352 month unavailable.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
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|US5800690 *||Jul 3, 1996||Sep 1, 1998||Caliper Technologies Corporation||Variable control of electroosmotic and/or electrophoretic forces within a fluid-containing structure via electrical forces|
|US5842787 *||Oct 9, 1997||Dec 1, 1998||Caliper Technologies Corporation||Microfluidic systems incorporating varied channel dimensions|
|US5858195 *||Aug 1, 1995||Jan 12, 1999||Lockheed Martin Energy Research Corporation||Apparatus and method for performing microfluidic manipulations for chemical analysis and synthesis|
|US5869004 *||Jun 9, 1997||Feb 9, 1999||Caliper Technologies Corp.||Methods and apparatus for in situ concentration and/or dilution of materials in microfluidic systems|
|US5876675 *||Aug 5, 1997||Mar 2, 1999||Caliper Technologies Corp.||Microfluidic devices and systems|
|US5882903 *||Nov 1, 1996||Mar 16, 1999||Sarnoff Corporation||Assay system and method for conducting assays|
|US5922617 *||Nov 12, 1997||Jul 13, 1999||Functional Genetics, Inc.||Rapid screening assay methods and devices|
|US5932100 *||Jun 14, 1996||Aug 3, 1999||University Of Washington||Microfabricated differential extraction device and method|
|US5939312 *||May 17, 1996||Aug 17, 1999||Biometra Biomedizinische Analytik Gmbh||Miniaturized multi-chamber thermocycler|
|US5942093 *||Jun 18, 1997||Aug 24, 1999||Sandia Corporation||Electro-osmotically driven liquid delivery method and apparatus|
|US5942443 *||Jun 28, 1996||Aug 24, 1999||Caliper Technologies Corporation||High throughput screening assay systems in microscale fluidic devices|
|US5944971 *||Apr 23, 1997||Aug 31, 1999||Lockheed Martin Energy Research Corporation||Large scale DNA microsequencing device|
|US5948227 *||Dec 17, 1997||Sep 7, 1999||Caliper Technologies Corp.||Methods and systems for performing electrophoretic molecular separations|
|US5953022 *||Jul 31, 1997||Sep 14, 1999||Eastman Kodak Company||Mechanical microfluidic printing array value|
|US5957579 *||Sep 30, 1998||Sep 28, 1999||Caliper Technologies Corp.||Microfluidic systems incorporating varied channel dimensions|
|US5958694 *||Oct 16, 1997||Sep 28, 1999||Caliper Technologies Corp.||Apparatus and methods for sequencing nucleic acids in microfluidic systems|
|US5961925 *||Sep 22, 1997||Oct 5, 1999||Bristol-Myers Squibb Company||Apparatus for synthesis of multiple organic compounds with pinch valve block|
|US5964995 *||Apr 4, 1997||Oct 12, 1999||Caliper Technologies Corp.||Methods and systems for enhanced fluid transport|
|US5964997 *||Mar 21, 1997||Oct 12, 1999||Sarnoff Corporation||Balanced asymmetric electronic pulse patterns for operating electrode-based pumps|
|US5965001 *||Jul 3, 1997||Oct 12, 1999||Caliper Technologies Corporation||Variable control of electroosmotic and/or electrophoretic forces within a fluid-containing structure via electrical forces|
|US5965410 *||Nov 25, 1997||Oct 12, 1999||Caliper Technologies Corp.||Electrical current for controlling fluid parameters in microchannels|
|US5971158 *||Jun 13, 1997||Oct 26, 1999||University Of Washington||Absorption-enhanced differential extraction device|
|US5976336 *||Apr 25, 1997||Nov 2, 1999||Caliper Technologies Corp.||Microfluidic devices incorporating improved channel geometries|
|US5978002 *||Jul 31, 1997||Nov 2, 1999||Eastman Kodak Company||High resolution microfluidic printing array valve|
|US5982401 *||Oct 3, 1997||Nov 9, 1999||Eastman Kodak Company||Microfluidic printing with controlled density|
|US5986679 *||Jul 31, 1997||Nov 16, 1999||Eastman Kodak Company||Microfluidic printing array valve with multiple use printing nozzles|
|US5986680 *||Aug 29, 1997||Nov 16, 1999||Eastman Kodak Company||Microfluidic printing using hot melt ink|
|US5989402 *||Aug 29, 1997||Nov 23, 1999||Caliper Technologies Corp.||Controller/detector interfaces for microfluidic systems|
|US6001229 *||Aug 1, 1994||Dec 14, 1999||Lockheed Martin Energy Systems, Inc.||Apparatus and method for performing microfluidic manipulations for chemical analysis|
|US6001231 *||Jul 15, 1997||Dec 14, 1999||Caliper Technologies Corp.||Methods and systems for monitoring and controlling fluid flow rates in microfluidic systems|
|US6004515 *||Oct 27, 1998||Dec 21, 1999||Calipher Technologies Corp.||Methods and apparatus for in situ concentration and/or dilution of materials in microfluidic systems|
|US6007690 *||Jul 30, 1997||Dec 28, 1999||Aclara Biosciences, Inc.||Integrated microfluidic devices|
|US6007775 *||Sep 26, 1997||Dec 28, 1999||University Of Washington||Multiple analyte diffusion based chemical sensor|
|US6008825 *||Aug 27, 1997||Dec 28, 1999||Eastman Kodak Company||Microfluidic printing independent of orientation|
|US6010607 *||Sep 16, 1998||Jan 4, 2000||Lockheed Martin Energy Research Corporation||Apparatus and method for performing microfluidic manipulations for chemical analysis and synthesis|
|US6010608 *||Sep 16, 1998||Jan 4, 2000||Lockheed Martin Energy Research Corporation||Apparatus and method for performing microfluidic manipulations for chemical analysis and synthesis|
|US6012902 *||Sep 25, 1997||Jan 11, 2000||Caliper Technologies Corp.||Micropump|
|US6033546 *||Sep 15, 1998||Mar 7, 2000||Lockheed Martin Energy Research Corporation||Apparatus and method for performing microfluidic manipulations for chemical analysis and synthesis|
|US6037955 *||Nov 14, 1997||Mar 14, 2000||Eastman Kodak Company||Microfluidic image display|
|US6037956 *||Feb 18, 1998||Mar 14, 2000||Eastman Kodak Company||Microfluidic printing apparatus having transparent ink receiving element|
|US6042208 *||Jun 3, 1997||Mar 28, 2000||Eastman Kodak Company||Image producing apparatus for microfluidic printing|
|US6042710 *||May 11, 1999||Mar 28, 2000||Caliper Technologies Corp.||Methods and compositions for performing molecular separations|
|US6043080 *||Dec 11, 1998||Mar 28, 2000||Affymetrix, Inc.||Integrated nucleic acid diagnostic device|
|US6044981 *||Aug 25, 1998||Apr 4, 2000||The Regents Of The University Of California||Microfabricated filter with specially constructed channel walls, and containment well and capsule constructed with such filters|
|US6046056 *||Dec 6, 1996||Apr 4, 2000||Caliper Technologies Corporation||High throughput screening assay systems in microscale fluidic devices|
|US6048498 *||Nov 12, 1998||Apr 11, 2000||Caliper Technologies Corp.||Microfluidic devices and systems|
|US6048734 *||Jul 3, 1997||Apr 11, 2000||The Regents Of The University Of Michigan||Thermal microvalves in a fluid flow method|
|US6054035 *||Jul 21, 1997||Apr 25, 2000||Hitachi, Ltd.||DNA sample preparation and electrophoresis analysis apparatus|
|US6055004 *||Jul 31, 1997||Apr 25, 2000||Eastman Kodak Company||Microfluidic printing array valve|
|US6056859 *||Feb 12, 1997||May 2, 2000||Lockheed Martin Energy Research Corporation||Method and apparatus for staining immobilized nucleic acids|
|US6056860 *||Sep 18, 1997||May 2, 2000||Aclara Biosciences, Inc.||Surface modified electrophoretic chambers|
|US6057149 *||Sep 15, 1995||May 2, 2000||The University Of Michigan||Microscale devices and reactions in microscale devices|
|US6068752 *||Aug 11, 1999||May 30, 2000||Caliper Technologies Corp.||Microfluidic devices incorporating improved channel geometries|
|US6072509 *||Jun 3, 1997||Jun 6, 2000||Eastman Kodak Company||Microfluidic printing with ink volume control|
|US6078340 *||Feb 3, 1998||Jun 20, 2000||Eastman Kodak Company||Using silver salts and reducing reagents in microfluidic printing|
|US6086740 *||Oct 29, 1998||Jul 11, 2000||Caliper Technologies Corp.||Multiplexed microfluidic devices and systems|
|US6091433 *||Jun 11, 1997||Jul 18, 2000||Eastman Kodak Company||Contact microfluidic printing apparatus|
|US6094207 *||Nov 13, 1997||Jul 25, 2000||Eastman Kodak Company||Microfluidic image display using melted ink|
|US6096656 *||Jun 24, 1999||Aug 1, 2000||Sandia Corporation||Formation of microchannels from low-temperature plasma-deposited silicon oxynitride|
|US6097406 *||May 26, 1998||Aug 1, 2000||Eastman Kodak Company||Apparatus for mixing and ejecting mixed colorant drops|
|US6100541 *||Feb 24, 1998||Aug 8, 2000||Caliper Technologies Corporation||Microfluidic devices and systems incorporating integrated optical elements|
|US6107044 *||Jun 16, 1999||Aug 22, 2000||Caliper Technologies Corp.||Apparatus and methods for sequencing nucleic acids in microfluidic systems|
|US6123798 *||May 6, 1998||Sep 26, 2000||Caliper Technologies Corp.||Methods of fabricating polymeric structures incorporating microscale fluidic elements|
|US6128027 *||Jun 3, 1997||Oct 3, 2000||Eastman Kodak Company||Continuous tone microfluidic printing|
|US6129826 *||May 11, 1999||Oct 10, 2000||Caliper Technologies Corp.||Methods and systems for enhanced fluid transport|
|US6129896 *||Dec 17, 1998||Oct 10, 2000||Drawn Optical Components, Inc.||Biosensor chip and manufacturing method|
|US6130098 *||Sep 26, 1997||Oct 10, 2000||The Regents Of The University Of Michigan||Moving microdroplets|
|US6132579 *||Jan 26, 1999||Oct 17, 2000||Eastman Kodak Company||Liquid separation|
|US6132685 *||Aug 10, 1998||Oct 17, 2000||Caliper Technologies Corporation||High throughput microfluidic systems and methods|
|US6143152 *||Nov 7, 1997||Nov 7, 2000||The Regents Of The University Of California||Microfabricated capillary array electrophoresis device and method|
|US6143496 *||Apr 17, 1997||Nov 7, 2000||Cytonix Corporation||Method of sampling, amplifying and quantifying segment of nucleic acid, polymerase chain reaction assembly having nanoliter-sized sample chambers, and method of filling assembly|
|US6148508 *||Mar 12, 1999||Nov 21, 2000||Caliper Technologies Corp.||Method of making a capillary for electrokinetic transport of materials|
|US6149787 *||Oct 14, 1998||Nov 21, 2000||Caliper Technologies Corp.||External material accession systems and methods|
|US6149870 *||Sep 28, 1999||Nov 21, 2000||Caliper Technologies Corp.||Apparatus for in situ concentration and/or dilution of materials in microfluidic systems|
|US6150119 *||Jan 19, 1999||Nov 21, 2000||Caliper Technologies Corp.||Optimized high-throughput analytical system|
|US6150180 *||Jul 26, 1999||Nov 21, 2000||Caliper Technologies Corp.||High throughput screening assay systems in microscale fluidic devices|
|US6153073 *||Aug 11, 1999||Nov 28, 2000||Caliper Technologies Corp.||Microfluidic devices incorporating improved channel geometries|
|US6156181 *||Oct 26, 1998||Dec 5, 2000||Caliper Technologies, Corp.||Controlled fluid transport microfabricated polymeric substrates|
|US6167910||Jan 14, 1999||Jan 2, 2001||Caliper Technologies Corp.||Multi-layer microfluidic devices|
|US6171067||Oct 20, 1999||Jan 9, 2001||Caliper Technologies Corp.||Micropump|
|US6171850||Mar 8, 1999||Jan 9, 2001||Caliper Technologies Corp.||Integrated devices and systems for performing temperature controlled reactions and analyses|
|US6174675||Aug 27, 1998||Jan 16, 2001||Caliper Technologies Corp.||Electrical current for controlling fluid parameters in microchannels|
|US6186660 *||Jul 26, 1999||Feb 13, 2001||Caliper Technologies Corp.||Microfluidic systems incorporating varied channel dimensions|
|US6221226||Oct 7, 1999||Apr 24, 2001||Caliper Technologies Corp.||Methods and systems for monitoring and controlling fluid flow rates in microfluidic systems|
|US6221677||Jun 18, 1999||Apr 24, 2001||University Of Washington||Simultaneous particle separation and chemical reaction|
|US6224830 *||Jan 30, 1998||May 1, 2001||The Governors Of The University Of Alberta||Absorbance cell for microfluid devices|
|US6235175||Oct 2, 1998||May 22, 2001||Caliper Technologies Corp.||Microfluidic devices incorporating improved channel geometries|
|US6235471||Apr 3, 1998||May 22, 2001||Caliper Technologies Corp.||Closed-loop biochemical analyzers|
|US6238538||Apr 6, 1999||May 29, 2001||Caliper Technologies, Corp.||Controlled fluid transport in microfabricated polymeric substrates|
|US6251343||Feb 24, 1998||Jun 26, 2001||Caliper Technologies Corp.||Microfluidic devices and systems incorporating cover layers|
|US6261431||Dec 28, 1998||Jul 17, 2001||Affymetrix, Inc.||Process for microfabrication of an integrated PCR-CE device and products produced by the same|
|US6267858 *||Jun 24, 1997||Jul 31, 2001||Caliper Technologies Corp.||High throughput screening assay systems in microscale fluidic devices|
|US6267859||Nov 8, 1999||Jul 31, 2001||Hitachi, Ltd||DNA sample preparation and electrophoresis analysis apparatus|
|US6267930||May 24, 1999||Jul 31, 2001||Waldemar Ruediger||Apparatus for synthesis of multiple organic compounds with pinch valve block|
|US6268219 *||Jul 9, 1999||Jul 31, 2001||Orchid Biosciences, Inc.||Method and apparatus for distributing fluid in a microfluidic device|
|US6274089||Jun 8, 1998||Aug 14, 2001||Caliper Technologies Corp.||Microfluidic devices, systems and methods for performing integrated reactions and separations|
|US6274094||Dec 16, 1997||Aug 14, 2001||Weller, Iii Harold Norris||Nestable, modular apparatus for synthesis of multiple organic compounds|
|US6274337||Mar 19, 1998||Aug 14, 2001||Caliper Technologies Corp.||High throughput screening assay systems in microscale fluidic devices|
|US6275245||Oct 3, 1997||Aug 14, 2001||Eastman Kodak Company||Controlling amount of ink pixels produced by microfluidic printing|
|US6277641||Nov 17, 1999||Aug 21, 2001||University Of Washington||Methods for analyzing the presence and concentration of multiple analytes using a diffusion-based chemical sensor|
|US6294063||Feb 12, 1999||Sep 25, 2001||Board Of Regents, The University Of Texas System||Method and apparatus for programmable fluidic processing|
|US6297061||Feb 10, 2000||Oct 2, 2001||University Of Washington||Simultaneous particle separation and chemical reaction|
|US6306590 *||Jun 8, 1998||Oct 23, 2001||Caliper Technologies Corp.||Microfluidic matrix localization apparatus and methods|
|US6306659||Nov 20, 1998||Oct 23, 2001||Caliper Technologies Corp.||High throughput screening assay systems in microscale fluidic devices|
|US6316201||Jun 21, 2000||Nov 13, 2001||Caliper Technologies Corp.||Apparatus and methods for sequencing nucleic acids in microfluidic systems|
|US6316781||Jun 16, 2000||Nov 13, 2001||Caliper Technologies Corporation||Microfluidic devices and systems incorporating integrated optical elements|
|US6321791||Oct 4, 2000||Nov 27, 2001||Caliper Technologies Corp.||Multi-layer microfluidic devices|
|US6322683||Apr 14, 1999||Nov 27, 2001||Caliper Technologies Corp.||Alignment of multicomponent microfabricated structures|
|US6325908 *||Aug 11, 1998||Dec 4, 2001||Hitachi, Ltd.||Electrophoresis analysis apparatus and sample vessel used therefor|
|US6326211||Mar 10, 2000||Dec 4, 2001||Affymetrix, Inc.||Method of manipulating a gas bubble in a microfluidic device|
|US6331439 *||Sep 14, 1998||Dec 18, 2001||Orchid Biosciences, Inc.||Device for selective distribution of liquids|
|US6337212||Nov 2, 2000||Jan 8, 2002||Caliper Technologies Corp.||Methods and integrated devices and systems for performing temperature controlled reactions and analyses|
|US6344326||Feb 10, 2000||Feb 5, 2002||Aclara Bio Sciences, Inc.||Microfluidic method for nucleic acid purification and processing|
|US6351274||Feb 16, 1999||Feb 26, 2002||Eastman Kodak Company||Continuous tone microfluidic printing|
|US6361958 *||Nov 12, 1999||Mar 26, 2002||Motorola, Inc.||Biochannel assay for hybridization with biomaterial|
|US6376181 *||Dec 14, 1999||Apr 23, 2002||Ut-Battelle, Llc||Method for analyzing nucleic acids by means of a substrate having a microchannel structure containing immobilized nucleic acid probes|
|US6379974||Aug 19, 1999||Apr 30, 2002||Caliper Technologies Corp.||Microfluidic systems|
|US6387707||May 28, 1999||May 14, 2002||Bioarray Solutions||Array Cytometry|
|US6391559||May 2, 2000||May 21, 2002||Cytonix Corporation||Method of sampling, amplifying and quantifying segment of nucleic acid, polymerase chain reaction assembly having nanoliter-sized sample chambers, and method of filling assembly|
|US6391622||Jun 27, 2000||May 21, 2002||Caliper Technologies Corp.||Closed-loop biochemical analyzers|
|US6394759||Nov 9, 2000||May 28, 2002||Caliper Technologies Corp.||Micropump|
|US6399025 *||Mar 21, 2000||Jun 4, 2002||Caliper Technologies Corp.||Analytical system and method|
|US6399389||Jul 7, 2000||Jun 4, 2002||Caliper Technologies Corp.||High throughput screening assay systems in microscale fluidic devices|
|US6403338||Jun 27, 2000||Jun 11, 2002||Mountain View||Microfluidic systems and methods of genotyping|
|US6406893||Nov 20, 2000||Jun 18, 2002||Caliper Technologies Corp.||Microfluidic methods for non-thermal nucleic acid manipulations|
|US6409900||Sep 19, 2000||Jun 25, 2002||Caliper Technologies Corp.||Controlled fluid transport in microfabricated polymeric substrates|
|US6413401||Jul 3, 1997||Jul 2, 2002||Caliper Technologies Corp.||Variable control of electroosmotic and/or electrophoretic forces within a fluid-containing structure via electrical forces|
|US6413782 *||Mar 19, 1998||Jul 2, 2002||Caliper Technologies Corp.||Methods of manufacturing high-throughput screening systems|
|US6416642 *||Feb 5, 1999||Jul 9, 2002||Caliper Technologies Corp.||Method and apparatus for continuous liquid flow in microscale channels using pressure injection, wicking, and electrokinetic injection|
|US6420143||Feb 13, 1998||Jul 16, 2002||Caliper Technologies Corp.||Methods and systems for performing superheated reactions in microscale fluidic systems|
|US6429025 *||Jun 24, 1997||Aug 6, 2002||Caliper Technologies Corp.||High-throughput screening assay systems in microscale fluidic devices|
|US6431476||Dec 21, 1999||Aug 13, 2002||Cepheid||Apparatus and method for rapid ultrasonic disruption of cells or viruses|
|US6432720 *||Oct 12, 2001||Aug 13, 2002||Caliper Technologies Corp.||Analytical system and method|
|US6435840||Dec 21, 2000||Aug 20, 2002||Eastman Kodak Company||Electrostrictive micro-pump|
|US6440284||Dec 17, 1999||Aug 27, 2002||Caliper Technologies Corp.||Methods and compositions for performing molecular separations|
|US6440645 *||Jul 20, 1998||Aug 27, 2002||Cambridge Sensors Limited||Production of microstructures for use in assays|
|US6440722||Jun 27, 2000||Aug 27, 2002||Caliper Technologies Corp.||Microfluidic devices and methods for optimizing reactions|
|US6440725||Dec 24, 1998||Aug 27, 2002||Cepheid||Integrated fluid manipulation cartridge|
|US6444461||Sep 20, 2000||Sep 3, 2002||Caliper Technologies Corp.||Microfluidic devices and methods for separation|
|US6447661||Oct 12, 1999||Sep 10, 2002||Caliper Technologies Corp.||External material accession systems and methods|
|US6447727||Nov 17, 1997||Sep 10, 2002||Caliper Technologies Corp.||Microfluidic systems|
|US6454924||Feb 23, 2001||Sep 24, 2002||Zyomyx, Inc.||Microfluidic devices and methods|
|US6454945||Nov 1, 2000||Sep 24, 2002||University Of Washington||Microfabricated devices and methods|
|US6465257||Nov 18, 1997||Oct 15, 2002||Caliper Technologies Corp.||Microfluidic systems|
|US6468761||Jan 5, 2001||Oct 22, 2002||Caliper Technologies, Corp.||Microfluidic in-line labeling method for continuous-flow protease inhibition analysis|
|US6468811||Oct 17, 2000||Oct 22, 2002||Bioarray Solutions||Light-controlled electrokinetic assembly of particles near surfaces|
|US6471841||Jul 11, 2000||Oct 29, 2002||Caliper Technologies Corp.||Methods and systems for enhanced fluid transport|
|US6475364||Feb 2, 2000||Nov 5, 2002||Caliper Technologies Corp.||Methods, devices and systems for characterizing proteins|
|US6475441||Sep 1, 2000||Nov 5, 2002||Caliper Technologies Corp.||Method for in situ concentration and/or dilution of materials in microfluidic systems|
|US6479299 *||Aug 12, 1998||Nov 12, 2002||Caliper Technologies Corp.||Pre-disposed assay components in microfluidic devices and methods|
|US6486075 *||Apr 27, 2000||Nov 26, 2002||Agere Systems Guardian Corp.||Anisotropic wet etching method|
|US6486901||Aug 29, 1997||Nov 26, 2002||Eastman Kodak Company||Microfluidic printing with gel-forming inks|
|US6488895||May 9, 2000||Dec 3, 2002||Caliper Technologies Corp.||Multiplexed microfluidic devices, systems, and methods|
|US6488897||May 1, 2001||Dec 3, 2002||Caliper Technologies Corp.||Microfluidic devices and systems incorporating cover layers|
|US6494230||Jun 8, 2001||Dec 17, 2002||Caliper Technologies Corp.||Multi-layer microfluidic devices|
|US6495104||Aug 19, 1999||Dec 17, 2002||Caliper Technologies Corp.||Indicator components for microfluidic systems|
|US6495369||Apr 7, 2000||Dec 17, 2002||Caliper Technologies Corp.||High throughput microfluidic systems and methods|
|US6498353||Oct 24, 2001||Dec 24, 2002||Caliper Technologies||Microfluidic devices and systems incorporating integrated optical elements|
|US6500323||Mar 26, 1999||Dec 31, 2002||Caliper Technologies Corp.||Methods and software for designing microfluidic devices|
|US6503757||Oct 12, 2001||Jan 7, 2003||Caliper Technologies Corp.||Analytical system and method|
|US6506609||May 11, 2000||Jan 14, 2003||Caliper Technologies Corp.||Focusing of microparticles in microfluidic systems|
|US6511853||Aug 2, 2000||Jan 28, 2003||Caliper Technologies Corp.||Optimized high-throughput analytical system|
|US6514399||Nov 28, 2000||Feb 4, 2003||Caliper Technologies Corp.||Controlled fluid transport in microfabricated polymeric substrates|
|US6514771||Oct 17, 2000||Feb 4, 2003||Bioarray Solutions||Light-controlled electrokinetic assembly of particles near surfaces|
|US6517234||Nov 2, 2000||Feb 11, 2003||Caliper Technologies Corp.||Microfluidic systems incorporating varied channel dimensions|
|US6524790||Jun 8, 1998||Feb 25, 2003||Caliper Technologies Corp.||Apparatus and methods for correcting for variable velocity in microfluidic systems|
|US6527933||Sep 20, 2000||Mar 4, 2003||Hitachi, Ltd.||DNA sample preparation and electrophoresis analysis apparatus|
|US6534013||Feb 15, 2000||Mar 18, 2003||Caliper Technologies Corp.||Microfluidic devices and systems|
|US6537501||Oct 28, 1999||Mar 25, 2003||University Of Washington||Disposable hematology cartridge|
|US6537771||Oct 6, 2000||Mar 25, 2003||Caliper Technologies Corp.||Use of nernstein voltage sensitive dyes in measuring transmembrane voltage|
|US6537799||Apr 21, 1999||Mar 25, 2003||Caliper Technologies Corp.||Electrical current for controlling fluid parameters in microchannels|
|US6540896||Aug 4, 1999||Apr 1, 2003||Caliper Technologies Corp.||Open-Field serial to parallel converter|
|US6541274||Oct 17, 2001||Apr 1, 2003||Caliper Technologies Corp.||Integrated devices and method of use for performing temperature controlled reactions and analyses|
|US6544734||Dec 9, 1999||Apr 8, 2003||Cynthia G. Briscoe||Multilayered microfluidic DNA analysis system and method|
|US6551836||Nov 15, 1999||Apr 22, 2003||Caliper Technologies Corp.||Microfluidic devices, systems and methods for performing integrated reactions and separations|
|US6551838||Mar 2, 2001||Apr 22, 2003||Microchips, Inc.||Microfabricated devices for the storage and selective exposure of chemicals and devices|
|US6558944 *||Jul 1, 1999||May 6, 2003||Caliper Technologies Corp.||High throughput screening assay systems in microscale fluidic devices|
|US6558960||Nov 21, 2000||May 6, 2003||Caliper Technologies Corp.||High throughput screening assay systems in microscale fluidic devices|
|US6568910||Apr 2, 2002||May 27, 2003||Caliper Technologies Corp.||Micropump|
|US6572830||Jun 21, 1999||Jun 3, 2003||Motorola, Inc.||Integrated multilayered microfludic devices and methods for making the same|
|US6573039||Aug 29, 2000||Jun 3, 2003||Cellomics, Inc.||System for cell-based screening|
|US6573089||Nov 2, 2000||Jun 3, 2003||Applera Corporation||Method for using and making a fiber array|
|US6575188||Sep 18, 2001||Jun 10, 2003||Handylab, Inc.||Methods and systems for fluid control in microfluidic devices|
|US6576194||Oct 28, 1999||Jun 10, 2003||University Of Washington||Sheath flow assembly|
|US6582576||Oct 7, 1999||Jun 24, 2003||Caliper Technologies Corp.||Controller/detector interfaces for microfluidic systems|
|US6592696||Jan 21, 1999||Jul 15, 2003||Motorola, Inc.||Method for fabricating a multilayered structure and the structures formed by the method|
|US6592821||May 10, 2001||Jul 15, 2003||Caliper Technologies Corp.||Focusing of microparticles in microfluidic systems|
|US6599736 *||Aug 24, 2001||Jul 29, 2003||Fraunhofer-Gesellschaft Zur Foerderung Der Angewandten Forschung E.V.||Configurable microreactor network|
|US6613512||Jun 8, 1998||Sep 2, 2003||Caliper Technologies Corp.||Apparatus and method for correcting for variable velocity in microfluidic systems|
|US6613513||Feb 22, 2000||Sep 2, 2003||Caliper Technologies Corp.||Sequencing by incorporation|
|US6613580||Jun 30, 2000||Sep 2, 2003||Caliper Technologies Corp.||Microfluidic systems and methods for determining modulator kinetics|
|US6613581||Aug 17, 2000||Sep 2, 2003||Caliper Technologies Corp.||Microfluidic analytic detection assays, devices, and integrated systems|
|US6616823||Feb 15, 2001||Sep 9, 2003||Caliper Technologies Corp.||Systems for monitoring and controlling fluid flow rates in microfluidic systems|
|US6620591||Apr 16, 1999||Sep 16, 2003||Cellomics, Inc.||System for cell-based screening|
|US6630353||Nov 21, 2000||Oct 7, 2003||Caliper Technologies Corp.||High throughput screening assay systems in microscale fluidic devices|
|US6632400||Jun 22, 2000||Oct 14, 2003||Agilent Technologies, Inc.||Integrated microfluidic and electronic components|
|US6632655||Feb 22, 2000||Oct 14, 2003||Caliper Technologies Corp.||Manipulation of microparticles in microfluidic systems|
|US6635470 *||Jan 7, 2000||Oct 21, 2003||Applera Corporation||Fiber array and methods for using and making same|
|US6648015||Oct 3, 2002||Nov 18, 2003||Caliper Technologies Corp.||Multi-layer microfluidic devices|
|US6649358||May 25, 2000||Nov 18, 2003||Caliper Technologies Corp.||Microscale assays and microfluidic devices for transporter, gradient induced, and binding activities|
|US6649404 *||Jun 8, 2000||Nov 18, 2003||Applera Corporation||Method for using and making a fiber array|
|US6656431||Oct 28, 1999||Dec 2, 2003||University Of Washington||Sample analysis instrument|
|US6660480||Mar 5, 2002||Dec 9, 2003||Ut-Battelle, Llc||Method for analyzing nucleic acids by means of a substrate having a microchannel structure containing immobilized nucleic acid probes|
|US6664104||Nov 7, 2001||Dec 16, 2003||Cepheid||Device incorporating a microfluidic chip for separating analyte from a sample|
|US6669831||May 10, 2001||Dec 30, 2003||Caliper Technologies Corp.||Microfluidic devices and methods to regulate hydrodynamic and electrical resistance utilizing bulk viscosity enhancers|
|US6670133||Jul 17, 2002||Dec 30, 2003||Caliper Technologies Corp.||Microfluidic device for sequencing by hybridization|
|US6671624||Nov 27, 2000||Dec 30, 2003||Cellomics, Inc.||Machine readable storage media for detecting distribution of macromolecules between nucleus and cytoplasm in cells|
|US6675817 *||Apr 24, 2000||Jan 13, 2004||Lg.Philips Lcd Co., Ltd.||Apparatus for etching a glass substrate|
|US6681788||Jan 24, 2002||Jan 27, 2004||Caliper Technologies Corp.||Non-mechanical valves for fluidic systems|
|US6695147||Oct 12, 1999||Feb 24, 2004||University Of Washington||Absorption-enhanced differential extraction device|
|US6703205||Mar 19, 2002||Mar 9, 2004||Caliper Technologies Corp.||Apparatus and methods for correcting for variable velocity in microfluidic systems|
|US6712925||Oct 28, 1999||Mar 30, 2004||University Of Washington||Method of making a liquid analysis cartridge|
|US6716588||Dec 8, 2000||Apr 6, 2004||Cellomics, Inc.||System for cell-based screening|
|US6720148||Feb 20, 2002||Apr 13, 2004||Caliper Life Sciences, Inc.||Methods and systems for identifying nucleotides by primer extension|
|US6727071||Feb 27, 1998||Apr 27, 2004||Cellomics, Inc.||System for cell-based screening|
|US6730072||May 30, 2001||May 4, 2004||Massachusetts Institute Of Technology||Methods and devices for sealing microchip reservoir devices|
|US6730516||Jul 29, 2002||May 4, 2004||Zyomyx, Inc.||Microfluidic devices and methods|
|US6733645||Apr 12, 2001||May 11, 2004||Caliper Technologies Corp.||Total analyte quantitation|
|US6739576||Dec 20, 2001||May 25, 2004||Nanostream, Inc.||Microfluidic flow control device with floating element|
|US6740219||May 10, 2001||May 25, 2004||Hitachi, Ltd.||Electrophoresis analysis apparatus and sample vessel used therefor|
|US6749734 *||Aug 28, 2000||Jun 15, 2004||The Regents Of The University Of California||Microfabricated capillary array electrophoresis device and method|
|US6752966||Sep 1, 2000||Jun 22, 2004||Caliper Life Sciences, Inc.||Microfabrication methods and devices|
|US6756019||Apr 6, 2000||Jun 29, 2004||Caliper Technologies Corp.||Microfluidic devices and systems incorporating cover layers|
|US6759191||Jan 21, 2003||Jul 6, 2004||Caliper Life Sciences, Inc.||Use of nernstein voltage sensitive dyes in measuring transmembrane voltage|
|US6773429||Oct 11, 2001||Aug 10, 2004||Microchips, Inc.||Microchip reservoir devices and facilitated corrosion of electrodes|
|US6773567||Sep 14, 2000||Aug 10, 2004||Caliper Life Sciences, Inc.||High-throughput analytical microfluidic systems and methods of making same|
|US6777184||May 11, 2001||Aug 17, 2004||Caliper Life Sciences, Inc.||Detection of nucleic acid hybridization by fluorescence polarization|
|US6779559||Nov 5, 2003||Aug 24, 2004||Caliper Life Sciences, Inc.||Non-mechanical valves for fluidic systems|
|US6787088||Dec 10, 2002||Sep 7, 2004||Caliper Life Science, Inc.||Controlled fluid transport in microfabricated polymeric substrates|
|US6797524||Oct 17, 2000||Sep 28, 2004||Bioarray Solutions Ltd.||Light-controlled electrokinetic assembly of particles near surfaces|
|US6821486||Feb 20, 1998||Nov 23, 2004||Sinvent As||Multiautoclave for combinatorial synthesis of zeolites and other materials|
|US6827831||Aug 26, 1998||Dec 7, 2004||Callper Life Sciences, Inc.||Controller/detector interfaces for microfluidic systems|
|US6830729||Nov 28, 2000||Dec 14, 2004||University Of Washington||Sample analysis instrument|
|US6835293 *||Jul 9, 2001||Dec 28, 2004||Greiner Bio-One Gmbh||Analysis system|
|US6849411||Nov 22, 2002||Feb 1, 2005||Caliper Life Sciences, Inc.||Microfluidic sequencing methods|
|US6849463||Dec 19, 2002||Feb 1, 2005||Microchips, Inc.||Microfabricated devices for the storage and selective exposure of chemicals and devices|
|US6852284||Oct 13, 2000||Feb 8, 2005||University Of Washington||Liquid analysis cartridge|
|US6852287||Sep 12, 2001||Feb 8, 2005||Handylab, Inc.||Microfluidic devices having a reduced number of input and output connections|
|US6855553||Oct 2, 2000||Feb 15, 2005||3M Innovative Properties Company||Sample processing apparatus, methods and systems|
|US6857449||Sep 30, 2003||Feb 22, 2005||Caliper Life Sciences, Inc.||Multi-layer microfluidic devices|
|US6858185||Aug 23, 2000||Feb 22, 2005||Caliper Life Sciences, Inc.||Dilutions in high throughput systems with a single vacuum source|
|US6875619||May 17, 2001||Apr 5, 2005||Motorola, Inc.||Microfluidic devices comprising biochannels|
|US6878540||Nov 7, 2001||Apr 12, 2005||Cepheid||Device for lysing cells, spores, or microorganisms|
|US6887693||Nov 7, 2001||May 3, 2005||Cepheid||Device and method for lysing cells, spores, or microorganisms|
|US6889165||Jul 2, 2002||May 3, 2005||Battelle Memorial Institute||Application specific intelligent microsensors|
|US6893879||Nov 7, 2001||May 17, 2005||Cepheid||Method for separating analyte from a sample|
|US6902883||May 6, 2003||Jun 7, 2005||R. Terry Dunlay||System for cell-based screening|
|US6911183||Mar 6, 2000||Jun 28, 2005||The Regents Of The University Of Michigan||Moving microdroplets|
|US6937323||Nov 7, 2001||Aug 30, 2005||Burstein Technologies, Inc.||Interactive system for analyzing biological samples and processing related information and the use thereof|
|US6939451||Aug 24, 2001||Sep 6, 2005||Aclara Biosciences, Inc.||Microfluidic chip having integrated electrodes|
|US6941202||Aug 19, 2003||Sep 6, 2005||Battelle Memorial Institute||Diagnostics/prognostics using wireless links|
|US6942771 *||Apr 21, 1999||Sep 13, 2005||Clinical Micro Sensors, Inc.||Microfluidic systems in the electrochemical detection of target analytes|
|US6949377 *||Dec 13, 2001||Sep 27, 2005||Ho Winston Z||Chemiluminescence-based microfluidic biochip|
|US6958245||Nov 28, 2001||Oct 25, 2005||Bioarray Solutions Ltd.||Array cytometry|
|US6960467||Dec 19, 2001||Nov 1, 2005||Clinical Micro Sensors, Inc.||Biochannel assay for hybridization with biomaterial|
|US6972172||May 21, 2001||Dec 6, 2005||Glycominds Ltd.||Combinatorial complex carbohydrate libraries and methods for the manufacture and uses thereof|
|US6976982||Jan 9, 2002||Dec 20, 2005||Microchips, Inc.||Flexible microchip devices for ophthalmic and other applications|
|US6977033||Jul 10, 2001||Dec 20, 2005||Board Of Regents, The University Of Texas System||Method and apparatus for programmable fluidic processing|
|US6977163||Jun 4, 2002||Dec 20, 2005||Caliper Life Sciences, Inc.||Methods and systems for performing multiple reactions by interfacial mixing|
|US6979553||Sep 5, 2003||Dec 27, 2005||Caliper Life Sciences, Inc.||Use of Nernstein voltage sensitive dyes in measuring transmembrane voltage|
|US6982149||Jun 23, 2003||Jan 3, 2006||Applera Corporation||Fiber array and methods for using and making same|
|US6986382||May 16, 2003||Jan 17, 2006||Cooligy Inc.||Interwoven manifolds for pressure drop reduction in microchannel heat exchangers|
|US6987018||Jul 30, 2002||Jan 17, 2006||Cepheid||Container for holding cells or viruses for disruption|
|US6989128||May 8, 2002||Jan 24, 2006||Caliper Life Sciences, Inc.||Apparatus for continuous liquid flow in microscale channels using wicking|
|US6991713 *||Jan 23, 2001||Jan 31, 2006||Whitehead Institute For Biomedical Research||Methods and apparatus for processing a sample of biomolecular analyte using a microfabricated device|
|US6991941||Oct 17, 2000||Jan 31, 2006||Bioarray Solutions Ltd.||Light-controlled electrokinetic assembly of particles near surfaces|
|US6992769||Nov 16, 2001||Jan 31, 2006||Nagaoka & Co., Ltd.||Apparatus and method for carrying out analysis of samples using semi-reflective beam radiation inspection|
|US6994151||Feb 12, 2003||Feb 7, 2006||Cooligy, Inc.||Vapor escape microchannel heat exchanger|
|US6994781||Jul 3, 2001||Feb 7, 2006||Baxter International Inc.||Medical system, method and apparatus employing MEMS|
|US6995845||Dec 10, 2001||Feb 7, 2006||Burstein Technologies, Inc.||Methods for detecting analytes using optical discs and optical disc readers|
|US7000684||Oct 6, 2003||Feb 21, 2006||Cooligy, Inc.||Method and apparatus for efficient vertical fluid delivery for cooling a heat producing device|
|US7010391||Mar 28, 2001||Mar 7, 2006||Handylab, Inc.||Methods and systems for control of microfluidic devices|
|US7017654||Aug 18, 2003||Mar 28, 2006||Cooligy, Inc.||Apparatus and method of forming channels in a heat-exchanging device|
|US7021369||Jan 29, 2004||Apr 4, 2006||Cooligy, Inc.||Hermetic closed loop fluid system|
|US7026131||Nov 15, 2002||Apr 11, 2006||Nagaoka & Co., Ltd.||Methods and apparatus for blood typing with optical bio-discs|
|US7033474 *||Jun 6, 2000||Apr 25, 2006||Caliper Life Sciences, Inc.||Microfluidic devices incorporating improved channel geometries|
|US7033542||Feb 14, 2003||Apr 25, 2006||Archibald William B||High throughput screening with parallel vibrational spectroscopy|
|US7033747||Apr 11, 2002||Apr 25, 2006||Nagaoka & Co., Ltd||Multi-parameter assays including analysis discs and methods relating thereto|
|US7033754||Dec 22, 2000||Apr 25, 2006||Illumina, Inc.||Decoding of array sensors with microspheres|
|US7037416||Jan 11, 2001||May 2, 2006||Caliper Life Sciences, Inc.||Method for monitoring flow rate using fluorescent markers|
|US7041509||Apr 2, 2002||May 9, 2006||Caliper Life Sciences, Inc.||High throughput screening assay systems in microscale fluidic devices|
|US7041510||Jan 24, 2001||May 9, 2006||Bioarray Solutions Ltd.||System and method for programmable illumination pattern generation|
|US7044196||Oct 6, 2003||May 16, 2006||Cooligy,Inc||Decoupled spring-loaded mounting apparatus and method of manufacturing thereof|
|US7050308||Jun 30, 2004||May 23, 2006||Cooligy, Inc.||Power conditioning module|
|US7056746||Mar 27, 2002||Jun 6, 2006||Bioarray Solutions Ltd.||Array cytometry|
|US7057704||Mar 16, 2002||Jun 6, 2006||Bioarray Solutions Ltd.||System and method for programmable illumination pattern generation|
|US7060171||Jul 24, 2002||Jun 13, 2006||Caliper Life Sciences, Inc.||Methods and systems for reducing background signal in assays|
|US7060431||Jun 24, 1999||Jun 13, 2006||Illumina, Inc.||Method of making and decoding of array sensors with microspheres|
|US7060445||Nov 22, 2000||Jun 13, 2006||Cellomics, Inc.||System for cell-based screening|
|US7061104||Jun 30, 2004||Jun 13, 2006||Cooligy, Inc.||Apparatus for conditioning power and managing thermal energy in an electronic device|
|US7061594||Nov 9, 2001||Jun 13, 2006||Burstein Technologies, Inc.||Disc drive system and methods for use with bio-discs|
|US7069952||Nov 12, 2002||Jul 4, 2006||Caliper Life Sciences, Inc.||Microfluidic devices and methods of their manufacture|
|US7070592||Jul 7, 2004||Jul 4, 2006||Massachusetts Institute Of Technology||Medical device with array of electrode-containing reservoirs|
|US7081190||May 24, 2002||Jul 25, 2006||Caliper Life Sciences, Inc.||Methods and compositions for performing molecular separations|
|US7083914||Nov 22, 1999||Aug 1, 2006||Bioarray Solutions Ltd.||Color-encoding and in-situ interrogation of matrix-coupled chemical compounds|
|US7086839||Sep 23, 2003||Aug 8, 2006||Cooligy, Inc.||Micro-fabricated electrokinetic pump with on-frit electrode|
|US7087148||Nov 13, 2000||Aug 8, 2006||Clinical Micro Sensors, Inc.||Binding acceleration techniques for the detection of analytes|
|US7087203||Nov 19, 2001||Aug 8, 2006||Nagaoka & Co., Ltd.||Methods and apparatus for blood typing with optical bio-disc|
|US7090001||May 16, 2003||Aug 15, 2006||Cooligy, Inc.||Optimized multiple heat pipe blocks for electronics cooling|
|US7091048||Oct 24, 2002||Aug 15, 2006||Parce J Wallace||High throughput screening assay systems in microscale fluidic devices|
|US7094354||Dec 19, 2002||Aug 22, 2006||Bayer Healthcare Llc||Method and apparatus for separation of particles in a microfluidic device|
|US7104312||Oct 30, 2003||Sep 12, 2006||Cooligy, Inc.||Method and apparatus for achieving temperature uniformity and hot spot cooling in a heat producing device|
|US7105300||Apr 14, 2003||Sep 12, 2006||Caliper Life Sciences, Inc.||Sequencing by incorporation|
|US7110094||Nov 16, 2001||Sep 19, 2006||Burstein Technologies, Inc.||Apparatus and method for carrying out analysis of samples using radiation detector output ratios|
|US7110345||Jul 6, 2004||Sep 19, 2006||Burstein Technologies, Inc.||Multiple data layer optical discs for detecting analytes|
|US7117098||Nov 27, 2000||Oct 3, 2006||Cellomics, Inc.||Machine-readable storage medium for analyzing distribution of macromolecules between the cell membrane and the cell cytoplasm|
|US7125711||Dec 19, 2002||Oct 24, 2006||Bayer Healthcare Llc||Method and apparatus for splitting of specimens into multiple channels of a microfluidic device|
|US7138032||Feb 6, 2003||Nov 21, 2006||Caliper Life Sciences, Inc.||Methods of fabricating polymeric structures incorporating microscale fluidic elements|
|US7144119||Jan 24, 2001||Dec 5, 2006||Bioarray Solutions Ltd.||System and method for programmable illumination pattern generation|
|US7150999||Mar 5, 2002||Dec 19, 2006||Califer Life Sciences, Inc.||Process for filling microfluidic channels|
|US7152616||Dec 4, 2003||Dec 26, 2006||Spinx, Inc.||Devices and methods for programmable microscale manipulation of fluids|
|US7156159||Jul 1, 2003||Jan 2, 2007||Cooligy, Inc.||Multi-level microchannel heat exchangers|
|US7156969||Nov 5, 2003||Jan 2, 2007||Caliper Life Sciences, Inc.||Microfluidic matrix localization apparatus and methods|
|US7157049||Nov 13, 2002||Jan 2, 2007||Nagaoka & Co., Ltd.||Optical bio-discs and fluidic circuits for analysis of cells and methods relating thereto|
|US7160423||Mar 4, 2003||Jan 9, 2007||Caliper Life Sciences, Inc.||Mixed mode microfluidic systems|
|US7161356||May 12, 2003||Jan 9, 2007||Caliper Life Sciences, Inc.||Voltage/current testing equipment for microfluidic devices|
|US7172897||Nov 5, 2001||Feb 6, 2007||Clinical Micro Sensors, Inc.||Devices and methods for biochip multiplexing|
|US7178386||Apr 9, 2004||Feb 20, 2007||Nanostream, Inc.||Parallel fluid processing systems and methods|
|US7188662||Feb 1, 2005||Mar 13, 2007||Cooligy, Inc.||Apparatus and method of efficient fluid delivery for cooling a heat producing device|
|US7192557||Dec 14, 2001||Mar 20, 2007||Handylab, Inc.||Methods and systems for releasing intracellular material from cells within microfluidic samples of fluids|
|US7192559||Aug 2, 2001||Mar 20, 2007||Caliper Life Sciences, Inc.||Methods and devices for high throughput fluid delivery|
|US7200088||Jan 10, 2002||Apr 3, 2007||Burstein Technologies, Inc.||System and method of detecting investigational features related to a sample|
|US7201012||Aug 18, 2003||Apr 10, 2007||Cooligy, Inc.||Remedies to prevent cracking in a liquid system|
|US7208320||Dec 13, 2002||Apr 24, 2007||Caliper Life Sciences, Inc.||Open-field serial to parallel converter|
|US7214300||Jun 4, 2001||May 8, 2007||Epocal Inc.||Integrated electrokinetic devices and methods of manufacture|
|US7217356||Aug 5, 2005||May 15, 2007||Fenwal, Inc.||Medical system, method and apparatus employing MEMS|
|US7221632||Jul 12, 2002||May 22, 2007||Burstein Technologies, Inc.||Optical disc system and related detecting methods for analysis of microscopic structures|
|US7226442||Oct 10, 2001||Jun 5, 2007||Microchips, Inc.||Microchip reservoir devices using wireless transmission of power and data|
|US7226562||Aug 2, 2005||Jun 5, 2007||University Of Washington||Liquid analysis cartridge|
|US7226734||Jun 28, 2002||Jun 5, 2007||Illumina, Inc.||Multiplex decoding of array sensors with microspheres|
|US7235373||Apr 11, 2003||Jun 26, 2007||Cellomics, Inc.||System for cell-based screening|
|US7238323||Dec 5, 2002||Jul 3, 2007||Caliper Life Sciences, Inc.||Microfluidic sequencing systems|
|US7241421||May 14, 2003||Jul 10, 2007||Ast Management Inc.||Miniaturized fluid delivery and analysis system|
|US7247274||Nov 12, 2002||Jul 24, 2007||Caliper Technologies Corp.||Prevention of precipitate blockage in microfluidic channels|
|US7251210||Jan 23, 2003||Jul 31, 2007||Burstein Technologies, Inc.||Method for triggering through disc grooves and related optical analysis discs and system|
|US7264702||Nov 5, 2003||Sep 4, 2007||Caliper Life Sciences, Inc.||Total analyte quantitation|
|US7270786||Dec 14, 2001||Sep 18, 2007||Handylab, Inc.||Methods and systems for processing microfluidic samples of particle containing fluids|
|US7276330||Apr 17, 2003||Oct 2, 2007||Caliper Technologies Corp.||Devices, systems and methods for time domain multiplexing of reagents|
|US7285411||Nov 22, 2000||Oct 23, 2007||Caliper Life Sciences, Inc.||High throughput screening assay systems in microscale fluidic devices|
|US7291504||Mar 10, 2003||Nov 6, 2007||Bioarray Solutions Ltd.||Assay involving detection and identification with encoded particles|
|US7293423||Feb 1, 2005||Nov 13, 2007||Cooligy Inc.||Method and apparatus for controlling freezing nucleation and propagation|
|US7312087||Jan 11, 2001||Dec 25, 2007||Clinical Micro Sensors, Inc.||Devices and methods for biochip multiplexing|
|US7316801||Sep 16, 2002||Jan 8, 2008||Caliper Life Sciences, Inc.||High throughput microfluidic systems and methods|
|US7323140||Feb 15, 2002||Jan 29, 2008||Handylab, Inc.||Moving microdroplets in a microfluidic device|
|US7332130||Feb 17, 2004||Feb 19, 2008||Handylab, Inc.||Heat-reduction methods and systems related to microfluidic devices|
|US7344865||Aug 11, 2006||Mar 18, 2008||Caliper Life Sciences, Inc.||Sequencing by incorporation|
|US7347617||Aug 19, 2003||Mar 25, 2008||Siemens Healthcare Diagnostics Inc.||Mixing in microfluidic devices|
|US7351303||Oct 9, 2003||Apr 1, 2008||The Board Of Trustees Of The University Of Illinois||Microfluidic systems and components|
|US7384603||Apr 5, 2002||Jun 10, 2008||Hte Aktiengesellschaft The High Throughput Experimentation Company||Device for archiving and analyzing of materials|
|US7387898 *||Oct 8, 1997||Jun 17, 2008||Burstein Technologies, Inc.||Apparatus and method for conducting assays|
|US7390464||Jul 26, 2004||Jun 24, 2008||Burstein Technologies, Inc.||Fluidic circuits for sample preparation including bio-discs and methods relating thereto|
|US7419784||Mar 27, 2003||Sep 2, 2008||Dubrow Robert S||Methods, systems and apparatus for separation and isolation of one or more sample components of a sample biological material|
|US7427512||Aug 3, 2004||Sep 23, 2008||Bioarray Solutions Ltd.||Light-controlled electrokinetic assembly of particles near surfaces|
|US7428200||Jul 20, 2007||Sep 23, 2008||Burstein Technologies, Inc.||Method for triggering through disc grooves and related optical analysis discs and system|
|US7435381||May 29, 2003||Oct 14, 2008||Siemens Healthcare Diagnostics Inc.||Packaging of microfluidic devices|
|US7438856||Jun 24, 2003||Oct 21, 2008||Zyomyx, Inc.||Microfluidic devices and methods|
|US7445766||Apr 10, 2006||Nov 4, 2008||Microchips, Inc.||Medical device and method for diagnostic sensing|
|US7455971||Nov 22, 2005||Nov 25, 2008||Illumina, Inc.||Multiplex decoding of array sensors with microspheres|
|US7459127||Feb 26, 2002||Dec 2, 2008||Siemens Healthcare Diagnostics Inc.||Method and apparatus for precise transfer and manipulation of fluids by centrifugal and/or capillary forces|
|US7459315||Apr 25, 2002||Dec 2, 2008||Cytonix Corporation||Miniaturized assembly and method of filling assembly|
|US7473551||May 20, 2005||Jan 6, 2009||Atonomics A/S||Nano-mechanic microsensors and methods for detecting target analytes|
|US7497846||Dec 6, 2004||Mar 3, 2009||Microchips, Inc.||Hermetically sealed microchip reservoir devices|
|US7497994||Mar 3, 2004||Mar 3, 2009||Khushroo Gandhi||Microfluidic devices and systems incorporating cover layers|
|US7507575||Jul 5, 2005||Mar 24, 2009||3M Innovative Properties Company||Multiplex fluorescence detection device having removable optical modules|
|US7521186||Sep 10, 2003||Apr 21, 2009||Caliper Lifesciences Inc.||PCR compatible nucleic acid sieving matrix|
|US7527763||Jul 5, 2005||May 5, 2009||3M Innovative Properties Company||Valve control system for a rotating multiplex fluorescence detection device|
|US7537590||Aug 1, 2005||May 26, 2009||Microchips, Inc.||Multi-reservoir device for transdermal drug delivery and sensing|
|US7539020||Feb 16, 2007||May 26, 2009||Cooligy Inc.||Liquid cooling loops for server applications|
|US7563621||Feb 17, 2003||Jul 21, 2009||Siemens Healhcare Diagnostics Inc||Absorbing organic reagents into diagnostic test devices by formation of amine salt complexes|
|US7566538||Jan 22, 2008||Jul 28, 2009||Caliper Lifesciences Inc.||Sequencing by incorporation|
|US7569346||May 3, 2005||Aug 4, 2009||Cepheid||Method for separating analyte from a sample|
|US7582080||Dec 1, 2005||Sep 1, 2009||Microchips, Inc.||Implantable, tissue conforming drug delivery device|
|US7591302||Dec 8, 2003||Sep 22, 2009||Cooligy Inc.||Pump and fan control concepts in a cooling system|
|US7595189||Jun 24, 2004||Sep 29, 2009||Applied Biosystems, Llc||Integrated optics fiber array|
|US7599184||Feb 16, 2007||Oct 6, 2009||Cooligy Inc.||Liquid cooling loops for server applications|
|US7604628||Sep 1, 2005||Oct 20, 2009||Microchips, Inc.||Multi-cap reservoir devices for controlled release or exposure of reservoir contents|
|US7615345||May 16, 2006||Nov 10, 2009||Bio Array Solutions Ltd.||Arrays formed of encoded beads having oligonucleotides attached|
|US7635572||Jun 9, 2004||Dec 22, 2009||Life Technologies Corporation||Methods for conducting assays for enzyme activity on protein microarrays|
|US7641779||May 23, 2005||Jan 5, 2010||Board Of Regents, The University Of Texas System||Method and apparatus for programmable fluidic processing|
|US7655129 *||Apr 12, 2004||Feb 2, 2010||Osmetech Technology Inc.||Binding acceleration techniques for the detection of analytes|
|US7666687||Aug 15, 2006||Feb 23, 2010||James Russell Webster||Miniaturized fluid delivery and analysis system|
|US7670559||Aug 19, 2002||Mar 2, 2010||Caliper Life Sciences, Inc.||Microfluidic systems with enhanced detection systems|
|US7674431||Sep 12, 2002||Mar 9, 2010||Handylab, Inc.||Microfluidic devices having a reduced number of input and output connections|
|US7709249||Jul 5, 2005||May 4, 2010||3M Innovative Properties Company||Multiplex fluorescence detection device having fiber bundle coupling multiple optical modules to a common detector|
|US7723123||May 31, 2002||May 25, 2010||Caliper Life Sciences, Inc.||Western blot by incorporating an affinity purification zone|
|US7727477 *||Nov 28, 2005||Jun 1, 2010||Bio-Rad Laboratories, Inc.||Apparatus for priming microfluidics devices with feedback control|
|US7731906||Aug 2, 2004||Jun 8, 2010||Handylab, Inc.||Processing particle-containing samples|
|US7749774||Aug 21, 2003||Jul 6, 2010||Michael Seul||Arrays formed of encoded beads having ligands attached|
|US7754150||Jul 2, 2003||Jul 13, 2010||Caliper Life Sciences, Inc.||Microfluidic analytic detection assays, devices, and integrated systems|
|US7776024||Oct 26, 2007||Aug 17, 2010||Microchips, Inc.||Method of actuating implanted medical device|
|US7794946||Feb 4, 1999||Sep 14, 2010||Life Technologies Corporation||Microarray and uses therefor|
|US7829025||Aug 2, 2004||Nov 9, 2010||Venture Lending & Leasing Iv, Inc.||Systems and methods for thermal actuation of microfluidic devices|
|US7853409||Jun 4, 2007||Dec 14, 2010||Cellomics, Inc.||System for cell-based screening|
|US7867767||Apr 6, 2009||Jan 11, 2011||3M Innovative Properties Company||Valve control system for a rotating multiplex fluorescence detection device|
|US7867776||May 6, 2004||Jan 11, 2011||Caliper Life Sciences, Inc.||Priming module for microfluidic chips|
|US7879019||Oct 26, 2007||Feb 1, 2011||Microchips, Inc.||Method of opening reservoir of containment device|
|US7887752||Jan 21, 2004||Feb 15, 2011||Illumina, Inc.||Chemical reaction monitor|
|US7913719||Jan 29, 2007||Mar 29, 2011||Cooligy Inc.||Tape-wrapped multilayer tubing and methods for making the same|
|US7914994||Feb 12, 2009||Mar 29, 2011||Cepheid||Method for separating an analyte from a sample|
|US7972778||Mar 11, 2004||Jul 5, 2011||Applied Biosystems, Llc||Method for detecting the presence of a single target nucleic acid in a sample|
|US7985386||Sep 29, 2008||Jul 26, 2011||Microchips, Inc.||Implantable medical device for diagnostic sensing|
|US7987022||Oct 13, 2005||Jul 26, 2011||Handylab, Inc.||Methods and systems for control of microfluidic devices|
|US8003926||Sep 5, 2008||Aug 23, 2011||3M Innovative Properties Company||Enhanced sample processing devices, systems and methods|
|US8007267||Jun 11, 2007||Aug 30, 2011||Affymetrix, Inc.||System and method for making lab card by embossing|
|US8007648||Apr 5, 2007||Aug 30, 2011||Lauks Imants R||Integrated electrokinetic devices and methods of manufacture|
|US8007738||May 21, 2010||Aug 30, 2011||Caliper Life Sciences, Inc.||Western blot by incorporating an affinity purification zone|
|US8012703||Jun 23, 2009||Sep 6, 2011||Life Technologies Corporation||Microarrays and uses therefor|
|US8039271||Feb 12, 2007||Oct 18, 2011||Bioarray Solutions, Ltd.||Assays employing randomly distributed microbeads with attached biomolecules|
|US8067159||Aug 13, 2007||Nov 29, 2011||Applied Biosystems, Llc||Methods of detecting amplified product|
|US8071056||Apr 29, 2005||Dec 6, 2011||The Regents Of The University Of Michigan||Thermal microvalves|
|US8071393||Jul 24, 2007||Dec 6, 2011||Bioarray Solutions, Ltd.||Method of analyzing nucleic acids using an array of encoded beads|
|US8075852||Jun 11, 2007||Dec 13, 2011||Affymetrix, Inc.||System and method for bubble removal|
|US8080380||Jul 23, 2004||Dec 20, 2011||Illumina, Inc.||Use of microfluidic systems in the detection of target analytes using microsphere arrays|
|US8124402||May 17, 2006||Feb 28, 2012||Bioarray Solutions, Ltd.||Encoded beads having oligonucleotides attached in arrays on a patterned surface|
|US8216513||Nov 20, 2009||Jul 10, 2012||Board Of Regents, The University Of Texas System||Method and apparatus for programmable fluidic processing|
|US8216980||Aug 8, 2005||Jul 10, 2012||Polymicro Technologies Llc||Method of making a micro-channel array device|
|US8247176||Mar 7, 2011||Aug 21, 2012||Cepheid||Method for separating an analyte from a sample|
|US8257925||May 16, 2011||Sep 4, 2012||Applied Biosystems, Llc||Method for detecting the presence of a single target nucleic acid in a sample|
|US8268603||Sep 22, 2005||Sep 18, 2012||Cepheid||Apparatus and method for cell disruption|
|US8278071||Aug 13, 2007||Oct 2, 2012||Applied Biosystems, Llc||Method for detecting the presence of a single target nucleic acid in a sample|
|US8309368||Jun 11, 2007||Nov 13, 2012||Bioarray Solutions, Ltd.||Method of making a microbead array with attached biomolecules|
|US8323887||Aug 16, 2006||Dec 4, 2012||James Russell Webster||Miniaturized fluid delivery and analysis system|
|US8337775||Sep 8, 2008||Dec 25, 2012||Siemens Healthcare Diagnostics, Inc.||Apparatus for precise transfer and manipulation of fluids by centrifugal and or capillary forces|
|US8383060 *||Mar 7, 2007||Feb 26, 2013||Koninklijke Philips Electronics N.V.||System-in-package platform for electronic-microfluidic devices|
|US8399259||Apr 28, 2010||Mar 19, 2013||Panasonic Corporation||Measuring device, measuring apparatus and method of measuring|
|US8399383||May 4, 2001||Mar 19, 2013||Yale University||Protein chips for high throughput screening of protein activity|
|US8403907||Oct 29, 2007||Mar 26, 2013||Microchips, Inc.||Method for wirelessly monitoring implanted medical device|
|US8403915||Oct 19, 2009||Mar 26, 2013||Microchips, Inc.||Multi-opening reservoir devices for controlled release or exposure of reservoir contents|
|US8460865||Apr 24, 2007||Jun 11, 2013||Illumina, Inc.||Multiplex decoding of array sensors with microspheres|
|US8481268||Nov 17, 2011||Jul 9, 2013||Illumina, Inc.||Use of microfluidic systems in the detection of target analytes using microsphere arrays|
|US8481901||Aug 22, 2011||Jul 9, 2013||3M Innovative Properties Company||Enhanced sample processing devices, systems and methods|
|US8486247||Oct 30, 2007||Jul 16, 2013||Osmetch Technology, Inc.||Use of microfluidic systems in the electrochemical detection of target analytes|
|US8551698||Aug 13, 2007||Oct 8, 2013||Applied Biosystems, Llc||Method of loading sample into a microfluidic device|
|US20090072332 *||Mar 7, 2007||Mar 19, 2009||Koniklijke Phillips Electronics N.V||System-in-package platform for electronic-microfluidic devices|
|US20090298049 *||Dec 1, 2008||Dec 3, 2009||Handylab, Inc.||Methods for sample tracking|
|US20120132313 *||Aug 24, 2007||May 31, 2012||Anubha Bhatla||Systems and methods for cutting materials|
|USRE43365||Sep 27, 2010||May 8, 2012||Lawrence Livermore National Security, Llc||Apparatus for chemical amplification based on fluid partitioning in an immiscible liquid|
|CN101095052B||Oct 25, 2005||Feb 8, 2012||索尼株式会社||生物测定设备和生物测定方法|
|DE10041853C1 *||Aug 25, 2000||Feb 28, 2002||Gmd Gmbh||Konfigurierbares Mikroreaktornetzwerk|
|DE10106952A1 *||Feb 15, 2001||Sep 5, 2002||Cognis Deutschland Gmbh||Chip-Reaktor|
|DE10106952C2 *||Feb 15, 2001||Jan 16, 2003||Cognis Deutschland Gmbh||Chip-Reaktor|
|DE10117274A1 *||Apr 6, 2001||Oct 17, 2002||Hte Ag The High Throughput Exp||Verfahren zur Analyse und Archivierung von Materialien|
|DE10117274B4 *||Apr 6, 2001||Mar 3, 2005||Hte Ag The High Throughput Experimentation Company||Verfahren zur Analyse und Archivierung von wenigstens einer Materialbibliothek|
|DE10117275A1 *||Apr 6, 2001||Oct 17, 2002||Hte Ag The High Throughput Exp||Vorrichtung zur Archivierung und Analyse von Materialien|
|DE10117275B4 *||Apr 6, 2001||Feb 24, 2005||Hte Ag The High Throughput Experimentation Company||Vorrichtung zur Archivierung und Analyse von Materialien|
|DE10122133A1 *||May 8, 2001||Jan 10, 2002||Agilent Technologies Inc||Integrated analytic microsystem combines microfluidic component, e.g. capillary, with microelectronic component including signal measurement and processing circuits|
|DE10122133B4 *||May 8, 2001||Jan 8, 2004||Agilent Technologies, Inc. (n.d.Ges.d.Staates Delaware), Palo Alto||Integriertes Mikrosystem|
|DE10127221A1 *||May 23, 2001||Nov 28, 2002||Lifebits Ag||Carrier, for analysis of chemical or biological sensor molecules, has geometrical surface layout for samples, according to scanning method|
|DE19929734B4 *||Jun 29, 1999||Oct 6, 2005||Agilent Technologies, Inc. (n.d.Ges.d.Staates Delaware), Palo Alto||Mikrofluidvorrichtung|
|EP2325294A2||Jun 7, 2001||May 25, 2011||The Regents Of the University of California||Visual-servoing optical microscopy|
|EP2409767A1||Jun 16, 2006||Jan 25, 2012||Biocartis SA||Modular cartridge, system and method for automated medical diagnosis|
|WO1998045929A1 *||Mar 30, 1998||Oct 15, 1998||Caliper Techn Corp||Methods and systems for enhanced fluid transport|
|WO1999024822A1 *||Nov 9, 1998||May 20, 1999||Functional Genetics Inc||Rapid screening assay methods and devices|
|WO2000042212A1 *||Jan 18, 2000||Jul 20, 2000||Caliper Techn Corp||Optimized high-throughput analytical system|
|WO2000043766A1 *||Jan 19, 2000||Jul 27, 2000||Caliper Techn Corp||Method and apparatus for continuous liquid flow in microscale channels using pressure injection, wicking, and electrokinetic injection|
|WO2000058724A1 *||Mar 28, 2000||Oct 5, 2000||Ecole Polytech||Microscale total analysis system|
|WO2000071746A1 *||May 19, 2000||Nov 30, 2000||Nongyue He||Novel method for producing microarray chip of chemical compound and the microarray chip of chemical compound produced thereby|
|WO2000073799A1 *||May 25, 2000||Dec 7, 2000||Caliper Techn Corp||Microscale assays and microfluidic devices for transporter, gradient induced, and binding activities|
|WO2001003834A1 *||Jun 20, 2000||Jan 18, 2001||Orchid Biosciences Inc||Method and apparatus for distributing fluid in a microfluidic device|
|WO2006031385A2 *||Aug 24, 2005||Mar 23, 2006||Mark W Bitensky||Particle separating devices, systems and methods|
| || |
|U.S. Classification||422/505, 436/43, 204/600, 204/450, 422/68.1, 422/552|
|International Classification||B01L3/00, C07K1/04, C40B40/06, B01L7/00, G01N33/543, C40B70/00, C12Q1/68, G01N33/53, C40B60/14, C12M1/34, B01J19/00, C40B40/10, G01N37/00|
|Cooperative Classification||Y10S436/807, Y10S436/805, C40B40/10, B01L2300/0874, B01J2219/005, B01J2219/00605, B01J2219/00659, B01L2300/1827, B01L2200/0605, B01J2219/00828, B01J2219/00495, B01J2219/00547, B01J2219/0068, G01N33/54366, B01L3/502707, B01L2400/0633, B01L2300/0806, B01L3/50273, B01L7/52, B01J2219/00353, B01L2300/087, C07K1/042, B01J2219/00831, B01J19/0093, B01L2400/0409, B01J2219/00351, B01L2400/0406, B01L3/5025, C40B60/14, B01L2300/0867, B01J2219/00698, C40B40/06, B01J2219/00488, B01J2219/00585, B01L2200/12, B01J2219/00826, B01L2300/0864, B01L2200/147, B01J2219/00637, B01J2219/00686, B01J2219/00891, B01L3/502715, B01J2219/00725, B01J2219/00722, B01J2219/00317, B01J2219/0059, B01J2219/00536, B01J2219/00315, B01J2219/00648, C40B70/00, B01F13/0059, B01L2400/0415, B01J2219/00621, B01L3/502738, B01J2219/00626, B01J2219/00612, B01J2219/00369, B01L2300/0803, B01J2219/00596, B01J2219/00389, B01J19/0046, B01J2219/00952|
|European Classification||B01L3/5027D, B01L3/5025, B01L3/5027E, B01L3/5027A, B01L7/52, C07K1/04A, B01J19/00R, B01J19/00C, G01N33/543K|
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